Mitigating microplastic-induced organ Damage: Mechanistic insights from the microplastic-macrophage axes

Abstract

We live in a world increasingly dominated by plastic, leading to the generation of microplastic particles that pose significant global health concerns. Microplastics can enter the body via ingestion, inhalation, and direct contact, accumulating in various tissues and potentially causing harm. Despite this, the specific cellular mechanisms and signaling pathways involved remain poorly understood. Macrophages are essential in absorbing, distributing, and eliminating microplastics, playing a key role in the body's defense mechanisms. Recent evidence highlights oxidative stress signaling as a key pathway in microplastic-induced macrophage dysfunction. The accumulation of microplastics generates reactive oxygen species (ROS), disrupting normal macrophage functions and exacerbating inflammation and organ damage. This review serves as the first comprehensive examination of the interplay between microplastics, macrophages, and oxidative stress. It discusses how oxidative stress mediates macrophage responses to microplastics and explores the interactions with gut microbiota. Additionally, it reviews the organ damage resulting from alterations in macrophage function mediated by microplastics and offers a novel perspective on the defense, assessment, and treatment of microplastic-induced harm from the viewpoint of macrophages.

1. Introduction

Microplastics (MP) refer to plastic particles with a diameter of less than 5 mm, while nanoplastics (NP) are defined as plastic particles with a diameter of less than 1 μm. These small plastic molecules primarily originate from the degradation of plastic items, wear and tear of automobile tires, washing of clothing, weathering of paint coatings, and leakage of pre-production pellets and powders [1,2]. As plastics are widely used in various fields, we gradually find ourselves living in a world filled with plastic. Since the mid-20th century, the production and use of plastics have exploded due to the development of industrialization [1]. According to statistics, global plastic production reached 400.3 million tons in 2022, with an annual growth rate of 2.4 % [3]. If this trajectory continues, it is estimated that around 12 billion metric tons of plastic waste could accumulate by 2050 [4]. The widespread presence of microplastics not only threatens ecosystems but may also have potential impacts on human health [1]. This growing concern is underscored by the fact that April 22, 2024, marks the 55th Earth Day, with the theme “Planet vs. Plastics,” highlighting that microplastic pollution is a significant global issue.

Humans are exposed to, ingest, and inhale a variety of microplastics every day (Fig. 1). Additionally, microplastics have the potential to transfer through the marine food chain to humans [5]. The extensive use of plastic items in production, processing, packaging, and storage [6] has led to microplastics and nanoplastics being found in many food and drinking water sources due to degradation from physical or chemical processes [7]. Currently, there is no relevant legislation to limit their concentration in food, leading to long-term exposure and ingestion of microplastics, which poses a threat to human health and ecological safety. A meta-analysis of existing data indicates that individuals may ingest between 0.10 and 5 g of microplastics per week [8].

Fig. 1.

Degradation of plastics into microplastics and their entry into the human body. Common plastic polymers, including polypropylene, polystyrene, polyethylene terephthalate, polyvinyl chloride, polyethylene, and polyurethane, degrade into microplastics. These microplastics are widely dispersed in the environment, including air, water, and soil. The primary pathways for their entry into the human body include ingestion through the gastrointestinal tract, inhalation through the lungs, and skin contact.

Microplastics can enter the human body typically involve three mechanisms: ingestion through the gastrointestinal tract, inhalation through the lungs, or skin contact [[9], [10], [11]]. Once microplastics enter the body, they can reach the bloodstream and distribute to various organs [12,13]. Different types of microplastics have been found in human tissues such as blood, liver, lungs, placenta, kidneys, spleen, sputum, and feces [14]. Over time, microplastics can build up and remain in the body, potentially causing serious lung damage, liver toxicity, immune system issues, and reproductive toxicity [10,15]. Studies have shown that, in addition to causing direct toxicity, micro/nanoplastics can interact with the mammalian immune system once inside the body, leading to indirect damage [3,5,7,16]. Moreover, microplastics possess a small specific surface area and often contain additives that can effectively adsorb or bind heavy metals, organic pollutants, and viruses, while also promoting the growth of harmful bacteria on their surfaces, increasing potential risks [17,18].

When foreign particles enter the human body at the cellular level, immune cells are among the first responders. Macrophages, a critical component of innate immunity, play an essential role in the intestinal barrier, alveolar-blood barrier, and skin barrier that microplastics must traverse before entering the body [11]. Macrophages can capture specific types of material with diameters up to 10 μm through phagocytosis, thereby minimizing the contamination of other body parts by particulate matter [19]. Additionally, macrophages function as antigen-presenting cells (APCs), facilitating T cell activation, which is crucial for recognition by lymphocytes [20,21]. Beyond their immune and phagocytic functions, macrophages play a part in tissue remodeling, clearing cellular debris, and maintenance of homeostasis [22].

Given the significance of macrophages in immune defense against microplastics, we summarize and discuss the interactions between microplastics and macrophages, as well as the microplastic-gut microbiota-macrophage axis. We focus on the mechanisms by which microplastics promote macrophage toxicity endpoints through changes in intracellular ROS, revealing that the accumulation of microplastics in macrophages can induce ROS production and initiate a cascade of cellular inflammatory signaling, which may lead to unprecedented harmful effects. We review the organ damage caused by microplastic-mediated alterations in macrophage function and explore ways to prevent their harmful effects, focusing on macrophages. Our aim is to enhance understanding of microplastics’ impact on human health.

2. Overview of microplastics

Plastics are a variety of synthetic or semi-synthetic polymer materials. Environmental polymer plastics are made up of different chemical polymers, with common examples including polypropylene (PP), polystyrene (PS), polyethylene terephthalate (PET), polyvinyl chloride (PVC), polyethylene (PE), and polyurethane (PUR) [20,23,24]. In addition to the base polymers, these materials often contain additional components, such as additives and plasticizers [25].

As human activities increasingly affect the environment, plastic production and use have continuously increased since the 1950s, coupled with poor waste management, resulting in global pollution [26]. In 1972, Carpenter et al. first observed tiny plastic particles in the ocean [27]. In 2004, the term “microplastics” was introduced by Thompson et al. [28]. The various environmental exposures throughout the plastic lifecycle have led to small plastics in different shapes (like spheres, fibers, and fragments), sizes (ranging from macro to micron), and compositions [25]. Plastics can be categorized by size into mega plastics (>1 m), large plastics (<1 m), mesoplastics (<2.5 cm), and microplastics (<5 mm) [10]. Microplastics can further degrade into nanoplastics (diameter <1000 nm) [16]. As a global pollutant, microplastics are distributed throughout the Earth's biosphere. On one hand, microplastics are widely present in all types of aquatic environments. Studies have shown that about 70 % of marine debris consists of plastic objects [29]. On the other hand, besides their presence in water environments, microplastics in the atmosphere are also increasing, even affecting local and regional climates, especially in areas with particularly high plastic concentrations in the air [30,31]. Because of their extensive spread and long-lasting nature in the environment, plastics are even referred to as “technofossils”. The potential marking of microplastics as an indicator of the Anthropocene era further underscores the profound impact humans have on the Earth's geological and soil ecosystems [31].

Microplastics can be produced intentionally (primary MP) or formed from larger plastics (secondary MP) through biodegradation and abiotic processes. Notably, abiotic processes primarily involve photodegradation, hydrolysis, mechanical degradation, or thermal degradation [10,20]. Once plastic products break down into microplastics, they become more dangerous than their original state, causing greater and more widespread harm to the ecological environment [31]. As their size decreases, microplastics can quickly bind with pollutants like heavy metals, organic substances, and microorganisms, facilitating the spread of these contaminants through the environment in different forms [29]. Microplastics are commonly found in marine ecosystems, making it easy for them to enter the human body through the seafood chain. Additionally, various food sources and everyday plastic food contact materials contain significant amounts of microplastics, indicating that human ingestion of microplastics is largely unavoidable [9,10]. Microplastics smaller than 20 μm can enter organs, while those smaller than 10 μm can pass through cell membranes and even cross the placental barrier in exposed cells or animals [32]. Therefore, as environmental microplastics degrade into smaller nanoplastics, there is an increased risk of penetrating organs, cell membranes, and tissues, allowing them to accumulate in organs and alter physiological processes [[33], [34], [35]].

Ingesting is the main pathway for microplastics, particularly nanoplastics, which can easily pass through cell membranes and the intestinal barrier into the bloodstream, subsequently relocating to other organs. Microplastics are also capable of penetrating the blood-brain barrier, accumulating in the brain, and exhibiting neurotoxicity [9]. Inhaled microplastics can cross the alveolar barrier and spread to organs via the bloodstream. Additionally, microplastics can be absorbed through skin contact with various topical agents [10]. Once in the bloodstream, microplastics can be redistributed to various organs. Microplastics have been found in a range of human tissue samples, such as feces, meconium, placenta, lung tissue samples, sputum, bronchoalveolar lavage fluid, breast milk, saliva, blood, face, liver, kidney, colon, and facial samples [10,36].

The exposure and accumulation of these microplastics can have harmful effects on multiple organs or organ systems [36], leading to tissue pathological changes and functional impairments in the digestive, respiratory, cardiovascular, immune, reproductive, and endocrine systems [37]. Moreover, microplastics exhibit transgenerational toxicity [38,39]. For instance, exposure to polystyrene microplastics (PS-MP) leads to induce physiological changes in Caenorhabditis elegans across subsequent generations [40]. Furthermore, microplastics have been demonstrated to transfer from mother to developing fetus in laboratory animals, as well as through analysis of human placentas. Maternal exposure to microplastics can alter offspring energy and lipid metabolism [10]. Some studies even indicate that maternal exposure to polystyrene nanoparticles (PS-NP) in mice results in abnormal brain development in offspring, increasing the risk of neurodevelopmental defects [41].

For humans, direct evidence linking microplastics to toxicity is still limited. In particular, there are no conclusive studies confirming the direct impact of microplastics or nanoplastics on diseases [37]. This lack of evidence may be attributed to the complexity of human metabolism and the possibility of low concentration exposure. Therefore, study on the potential negative effects of microplastics on organisms sometimes yields seemingly contradictory results. Recent research on the toxicity of microplastics to mammalian cells suggests that they may not be as damaging as initially thought, with effects typically occurring only at concentrations significantly higher than those found in the environment [15]. Additionally, over 90 % of ingested microplastics are excreted through feces [42]. On the other hand, the use of microplastics in the biomedical field appears beneficial. Due to their unique physicochemical properties of, nanoplastics have been actively and widely utilized as antigen carriers, imaging markers, and therapeutic drugs for disease diagnosis and treatment [43]. However, it is essential to recognize that microplastic pollution is characterized by low-dose, repetitive exposure. Over time, with the accumulation of microplastics in the body, there may be an increasing in high-burden microplastic cell populations, particularly in macrophages [19]. This review examines the toxic impact of microplastics on macrophages and the potential harmful consequences for various organ systems. Moreover, it explores strategies to target macrophages in order to prevent and mitigate the harm caused by microplastics.

3. Macrophages: a critical barrier for defending against and internalizing microplastic particles

Macrophages can be found in almost every tissue throughout the body [20]. They are known by different names depending on the tissue they inhabit, such as alveolar macrophages in the lungs, microglia in the nervous system, osteoclasts in bones, and Kupffer cells in the liver. These cells are crucial for the development of tissue and organ, injury repair, homeostasis, and the prevention of pathogens, chronic inflammation, fibrosis, and cancer [44]. Macrophages react to cues from their surroundings through polarization, making them crucial regulators and active participants in the immune system, providing timely immune responses. They can differentiate into various phenotypes and perform specific functions in diverse microenvironments [21]. Macrophages are essential in the gut barrier, lung air-blood barrier, and skin barrier, all of which are key entry points for microplastics into the human body. As the primary phagocytes in these mucosal environments and the most abundant cell type in the innate immune system, macrophages are vital for detecting and clearing pathogenic endogenous and exogenous chemicals across various tissues [45], acting as a key defense against microbes and environmental toxins [9,46]. Additionally, macrophages can act as carriers, transporting microplastic particles to different tissues [47]. Therefore, if these sentinel soldiers of immune defense fail, they could turn into a “Trojan horse”, inadvertently aiding in the breakdown of the body's defenses.

Once microplastics enter the body, the organism first activates physical defenses, such as mucus secretion, followed by the recruitment of immune cells, particularly macrophages. A study on the distribution and bioaccumulation of nanoplastics found a significant presence of these particles within macrophages [48]. Macrophages are key players in the innate immune defense against foreign particles, being specifically responsible for their internalization. They can directly internalize microplastic particles up to 10 μm in diameter and are crucial for the cellular uptake of microplastics [19,49,50]. Research has investigated the cellular absorption and toxic effects of microplastics derived from synthetic polymers (including PS, PE, and PVC) as well as bio-derived polymers (such as PLA and cellulose acetate [CA]) within the size range of 1–4 μm on mouse macrophages and epithelial cells [51]. Despite variations in particle characteristics, such as ζ potential, surface morphology, and varying uptake rates [10], macrophages successfully internalize all the tested particles [51]. Although these findings support the notion that macrophages can uptake microplastics and that microplastics have certain toxic effects on macrophages, further research is needed to explore the relationship between cellular uptake and toxicity. It appears that the toxic effects of microplastics are related to subsequent accumulation.

Studies indicate that macrophages internalize microplastics but do not degrade them [46]. Once internalized, these microplastics accumulate in lysosomes [10,45]. While microplastic particles can be passively released following macrophage death, no active excretion by live macrophages has been observed. Therefore, as long as the macrophages remain viable, the ingested particles persist, potentially leading to accumulation [49]. Accumulation of microplastics in lysosomes may result in lysosomal enzyme leakage and trigger inflammatory immune responses [45]. Furthermore, microplastics can cause lysosomal damage, prompting macrophage to reprogram and produce interleukin-1β (IL-1β) [7]. Research shows that microplastics from plastic food packaging (primarily PP and PET) are readily phagocytosed by alveolar macrophages, inducing inflammation and inhibiting lysosomal activity, thereby affecting the lysosomal digestion of autophagosomes and phagocytosed debris [52].

Macrophages have a dual function in the immune response, not only phagocytosing pathogens but also acting as immune effectors by presenting antigens and releasing both pro-inflammatory and anti-inflammatory cytokines [11]. Since antigen presentation and the secretion of inflammatory mediators by macrophages depend on the antigens they ingest, any impairment in their phagocytic function can compromise their overall immune effectiveness [53]. Continuous phagocytosis of indigestible microplastics can lead to rapid depletion of macrophages. The duration for the host to identify and clear these locally exhausted macrophages and replace them with new ones exceeds the normal duration needed for inflammation in response to pathogenic antigens, resulting in a temporary stagnation of host defense [54]. Furthermore, the inability of the immune system to clear microplastics may result in chronic inflammation and an increased risk of tumor development [55].

Additionally, the accumulation of microplastic particles within macrophages enhances their chemotactic migration, enabling these macrophages to enter the bloodstream and relocate to various macrophage-rich organs [19]. The presence of these high-load microplastic macrophage populations may have potentially harmful consequences for different organs and tissues throughout the body. Given that macrophages can undergo reversible phenotypic polarization in response to microenvironmental stimuli, transforming into either M1 macrophages that release pro-inflammatory cytokines or M2 macrophages that release anti-inflammatory cytokines [44], it is crucial to understand the toxic, metabolic, and functional effects of microplastics on macrophages (Fig. 2).

Fig. 2.

Influence of ROS induced by microplastics on macrophage metabolism, function, and polarization. When macrophages ingest microplastics (MPs), the subsequent generation of reactive oxygen species (ROS) triggers a spectrum of cell death modalities, encompassing apoptosis, necrosis, ferroptosis, pyroptosis, and autophagic cell death. For example, MPs stimulate ROS production, leading to the upregulation of Bax, subsequently activates caspase 9 and caspase 3, thereby intensifying the apoptotic cascade. Additionally, MPs elevate mitochondrial ROS levels, which in turn activate necrosomes, initiating necrotic cell death. Moreover, MPs facilitate cell ferroptosis by augmenting ROS accumulation and lipid peroxidation. Simultaneously, NLRP3 becomes activated and engages with ASC, resulting in the proteolytic maturation of caspase-1. This matured caspase-1 then converts pro-IL-1β and pro-IL-18 into their active forms, IL-1 β and IL-18, respectively, thereby inducing pyroptosis. Furthermore, MP-induced ROS contribute to the formation of protein misfolding aggregates, inducing endoplasmic reticulum (ER) stress. ROS also phosphorylates AMP-activated protein kinase (AMPK) and inhibits the AKT/mammalian target of rapamycin (mTOR) pathway, both actions reinforcing autophagic cell death. Notably, MP-triggered ROS initiates persistent mitophagy, causing lysosomal damage that liberates calcium ions. These calcium ions promote histone citrullination, thereby further inducing chromatin decondensation. Additionally, the activation of NF-κB signaling enhances the production of inflammatory cytokines, including TNF-α, IL-6, and IL-8, amplifying the inflammatory response and exacerbating cellular injury and demise. The interaction between nitric oxide (NO) and ROS further intensifies oxidative stress, disrupting iron homeostasis and promoting ferroptosis. Furthermore, ROS promotes the polarization of macrophages towards the pro-inflammatory M1 phenotype, thereby augmenting the inflammatory response and cell death.

4. The effects of microplastics on macrophage viability, metabolism, and functional polarization

4.1. The toxic effects of microplastics on macrophages due to their varying physicochemical properties and environmental exposure

The toxicity of microplastics is affected by particle size, concentration, and exposure duration [56,57]. Their toxic effects on macrophages also exhibit dependencies on these factors [11]. Smaller particles, higher concentrations, and longer exposure durations result in stronger cytotoxicity of microplastic particles [58]. Several in vivo and in vitro studies have demonstrated that upon exposure to PS-NPs, the cytotoxicity to macrophages increases as particle size decreases [20,59,60]. This indicates that particle size plays a crucial role in determining the toxic effects of microplastic particles on macrophages [61]. Additionally, macrophages absorb microplastics based on concentration, resulting in cytotoxic effects [11,62]. Studies have reported that macrophages exposed to PS-NPs at concentrations exceeding those currently found in human blood exhibit significantly increased necrosis [11,21]. Moreover, other studies have found that microplastics sized 0.5 mm are toxic to zebrafish macrophages at a concentration of 0.2 mg/mL, whereas 5 mm microplastics show toxicity at 0.5 mg/mL. These results highlight the significance of size and concentration as critical determinants of microplastic toxicity to macrophages [63].

However, some studies have reported contradictory results. For instance, a study involving mouse macrophages (J774A.1, ImKC) interacting with PS microplastic particles of varying sizes (0.2–6.0 μm) found that while macrophages actively phagocytosed microplastic particles of all sizes, no cytotoxic effects or impacts on cell proliferation were observed [64]. Similarly, another study that evaluated the cytotoxic effects of raw microplastic particles ranging from 1 to 4 μm, made from PS, PE, and PVC, as well as bio-derived polymer particles such as PLA and CA, concluded that these model polymer particles did not exhibit significant short-term cytotoxicity on mouse macrophages and epithelial cells [51]. These contradictory findings suggest that, in addition to concentration, size, and exposure duration, the pathophysiological effects of microplastics may also depend on factors such as polymer type, shape, environmental exposure, surface physicochemical properties, and interactions with surrounding proteins [10,47,58,[65], [66], [67]] (Table 1). Once ingested, microplastics can undergo extreme biochemical conditions in the gastrointestinal tract, resulting in the development of a unique protein corona on their surface. This protein corona, which is related to gastrointestinal digestion, may enhance the absorption by THP-1 derived human macrophages [68]. Furthermore, microplastic particles that have been environmentally exposed are more readily internalized by macrophages compared to raw microplastic particles. Research indicates that environmental exposure promotes the formation of an eco-corona of biomolecules on the surface of microplastic particles, facilitating their cellular internalization [47,50]. Additionally, the biological response of macrophages differs between aged and raw microplastics. Aged microplastics are more likely to cause greater cytotoxicity, heightened oxidative stress, and increased genotoxicity [49,65]. A study involving the mouse liver macrophage cell line ImKC exposed to either raw or weathered PS-MP demonstrated that although both types of microplastics were similarly absorbed by macrophages, only long-term weathered microplastics caused dose-dependent cytotoxic effects. In contrast, raw and briefly weathered microplastics primarily triggered inflammatory reactions based on concentration [15]. Moreover, the toxic effects of microplastics on macrophages vary with different surface functionalizations. In a PSNP study, RAW 264.7 mouse macrophages exhibited no cytotoxicity at 100 μg/mL after 24 h of treatment. However, surface functionalization with carboxyl (-COOH) and amino (-NH2) groups significantly enhanced cytotoxicity, causing significant cell death at concentrations of 20 μg/mL and 1 μg/mL, respectively [45]. Additionally, nanoplastics with a positive zeta potential tend to be more toxic than those with a negative zeta potential, likely because of their stronger interactions with the cell membrane [58]. Conversely, some studies have indicated that high-concentration microplastics with a higher negative zeta potential can adversely affect cell proliferation and induce greater cytotoxicity in mouse macrophages [69].

Table 1.

The factors influencing microplastic-induced macrophage toxicity.

Type	Treatment	Size	Concentration	Cell Type	Toxicity Effects	References
PS	Original	Under 450 nm	50–500 μg/mL	Human monocyte THP-1	Significantly reduced cell viability. Induced oxidative stress and decreased cell proliferation. Reduced mitochondrial membrane potential and caused DNA damage in macrophages.	[21]
PS	Original	0.2, 2, and 10 μm	10 μg/mL	HMC-3 (Human microglia cell)	Affects cell proliferation. Increased phagocytosis and apoptosis. Affects cell activation. Alters transcription of immune-related genes.	[70]
PS	Original	29, 44, and 72 nm	0–100 μg/mL	PBMC (Human peripheral blood mononuclear cells)	Increased ROS levels, leading to increased apoptosis and reduced PBMC viability.	[71]
PS	Original	50 nm and 500 nm	10 μg/mL and 50 μg/mL	Mouse macrophage cell line RAW264.7	PS-NPs at 50 μg/mL, 50 nm and 500 nm can induce macrophage polarization to M1 type.	[72]
PS	ζ potential (−41 ± 3 mV to −56 ± 2 mV)	29, 44, and 72 nm	0–100 μg/mL	PBMC	Caused reduced metabolic activity and DNA damage.	[73]
PS	Original, carboxyl-functionalized (PS–COOH), and amino-functionalized (PS–NH2)	PS and PS-COOH (approximately 100 nm), PS-NH (approximately 150 nm)	1–100 μg/mL	RAW264.7	PS-COOH and PS-NH2 reduced cell viability, induced oxidative stress, altered mitochondrial membrane potential, and induced apoptosis.	[45]
PS	Original, PS-COOH, PS-NH2	60 nm	0–40 μg/mL	RAW264.7	PS-NH2 can induce autophagic cell death.	[74]
PS	Original, PS-NH2, PS-COOH; disease-specific plasma protein induced	128.4 ± 1.15 (PS), 103.7 ± 1.15 (PS–NH2), and 109.8 ± 2.56 (PS–COOH)	100 μg/mL	THP-1	Cancer-specific protein corona promotes NP phagocytosis by macrophages, leading to a strong pro-inflammatory effect and promoting tumorigenesis.	[75]
PS	Sulfate-modified (S-NPs)	200 nm	100 μg/mL	RAW 264.7 and THP-1	Induced lipid accumulation accompanied by mitochondrial oxidative stress.	[22]
PS	Cadmium pre-treatment	0.5 μm and 1 μm	0–100 μg/mL	RAW264.7	Cadmium pre-treatment exacerbated the harmful effects of PS-MP on cell membrane systems, such as morphological changes and complete rupture of simulated lipid membranes.	[76]
PS	Original and photo-aged	456 ± 303 nm and 465 ± 212 nm	0.01–10 μg/mL	RAW264.7	Photo-aging of PS amplified the inflammatory response in macrophages.	[77]
PS	Original and oxidized (simulating aging process)	1 μm and 0.1 μm	25–100 μg/mL	Monocyte THP-1 and macrophage-like mTHP-1 cells	Significant increases in ROS and DNA damage were observed after exposure to oxidized particles.	[65]
PS	Original and PS-FBS protein complex (protein corona)	300 nm	150 μg/mL	RAW264.7	Pre-formed FBS protein corona alleviated PS-induced autophagosome accumulation and lysosomal damage.	[66]
PS	Original and artificially weathered	1.21 μm–1.80 μm	15 μg/mL and 150 μg/mL	Mouse liver macrophage cell line ImKC	Weathered MPs exhibited increased cytotoxic potential with higher inflammatory potential.	[15]
PS	Original and environmentally exposed (freshwater and saltwater)	3 μm	29,000 particles/23,000 cells	Mouse macrophage cell line J774A.1	Ecological corona formed under environmental conditions facilitated the intracellular uptake of microplastics.	[50]
Polypropylene (PP) and Polyvinyl Chloride (PVC)	Doped with cadmium selenide quantum dots (CdSe-QDs NPs)	50–350 nm	0–100 μg/mL	THP-1	Induced lipid metabolic disorders.	[78]
PP and PS	Original and weathered	100 μm	0–150 μg/mL	THP-1	Promoted ROS-induced cytotoxicity.	[79]
Polyethylene (PE)	Original and UV-irradiated degraded PE	231.4 μm and 231.9 μm	40–80 mg/mL	RAW 264.7 and THP-1	Degraded PE exposure led to lysosomal dysfunction resulting in cell death.	[80]
Polytetrafluoroethylene (PTFE)	Original	6.0 or 31.7 μm	1–1000 μg/mL	Monocyte cell lines U937 and THP-1	Induced oxidative stress (by increasing NO and ROS levels) and inflammation (by altering pro-inflammatory cytokine levels).	[81]
Polyethylene Terephthalate (PET), Low Density Polyethylene (LDPE), PP, and PS	Fragment leachate	410.9, 373.5, 722.6, and 400.6 nm	4 μg/mL	RAW264.7	Inhibited lysosomal activity in mouse macrophages.	[52]
PET	Original	163.01 nm	0–100 μg/mL	Mouse alveolar macrophages (MH-S)	Induced mitochondrial dysfunction, increased intracellular ROS levels, and macrophage polarization.	[82]
PET	Original, UV irradiation, and ultrasound exposure	18.9 μm (original) and 10.2 μm (UV/US treated)	1–500 μg/mL	THP-1	UV/US treated PET fragments enhanced inflammatory responses.	[83]

These seemingly contradictory experimental results suggest that the uptake and toxicity of microplastics by macrophages must be understood in the context of the physicochemical properties and environmental conditions of the microplastics themselves, rather than being attributed to a single factor. One perspective suggests that cellular uptake may be higher in the absence of smaller protein particles [84]. Considering the relationship between cellular uptake and microenvironmental factors, future research should focus on how molecules in the microenvironment, such as metals and proteins, influence the uptake and effects of microplastics. Moreover, most studies on the cellular internalization of microplastics use fluorescently labeled particles, which can leach out or even exhibit toxicity themselves, potentially leading to significant errors in the results [11]. In conclusion, there is a pressing need for more comprehensive research on the toxicity variations of microplastics with different physicochemical properties or following environmental exposure. Additionally, more refined experimental techniques should be developed to investigate cytotoxic effects, enabling a better understanding of the toxic impacts of microplastics on macrophages.

4.2. The effects of microplastics on macrophage metabolism and polarization

Microplastics can significantly alter the cellular metabolism of macrophages. Upon phagocytosis of microplastics, macrophages transition from a metabolically oxidative resting state to glycolysis, which is accompanied by a reduction in mitochondrial respiration. This metabolic shift is positively correlated with an increase in the expression of costimulatory molecules CD80 and CD86 on the cell surface, as well as the upregulation of pro-inflammatory cytokine genes [46].

In addition to altering metabolism, microplastics can activate and differentiate macrophages. They promote macrophage aggregation [85] and facilitate their maturation [12]. For instance, nanoplastics can penetrate bone marrow, impairing the migration capacity of pre-osteoblasts while enhancing osteoclastogenesis of pre-osteoclasts, thereby increasing the differentiation of RAW264.7 cells into osteoclasts at the morphological and molecular levels.

Furthermore, microplastics induce polarization of macrophages towards the M1 phenotype. Studies have demonstrated that exposure to PS-M/NPs alters surface markers expression on mouse macrophages [19,46]. Specifically, microplastics enhance CD80 expression in RAW264.7 cells, indicating a transition to a pro-inflammatory phenotype [7]. Some studies have also reported a concentration-dependent effect, with lower concentrations of PS-NPs inducing a weaker pro-inflammatory response [86,87]. Gu et al. [88] observed that exposure to PS-M/NPs (100 nm, 5 μm, and 200 μm, 500 μg/L) led to an increase in the proportion of M1 macrophages and a decrease in M2 macrophages in the intestines of adult zebrafish. Additionally, research examining the long-term oral intake of microplastics in mice revealed increased macrophage infiltration in the liver, significantly raising the percentage of M1 macrophages while decreasing the proportion of M2 macrophages [89]. A recent study further demonstrated that PS-NPs promote M1 polarization of mouse RAW264.7 macrophages, regardless of size, identifying 50 μg/mL as a critical concentration threshold. Exceeding this concentration significantly affects macrophage activity, promoting M1 polarization while inhibiting M2 polarization [72]. Collectively, these findings indicate that microplastics can effectively induce a dominant M1 polarization state in macrophages.

4.2.1. The pro-inflammatory effects of microplastics on macrophages

The inflammatory response is a critical mechanism underlying microplastic-induced cytotoxicity [37]. Macrophages, as key immune cells involved in inflammation, have been demonstrated in various in vitro and in vivo studies to exhibit pro-inflammatory responses upon exposure to microplastics. For example, Das et al. [10] showed that PS-NPs in the air can promote the release of inflammatory proteins like tumor necrosis factor- α (TNF-α), IL-6, and IL-1β in mouse alveolar macrophages. Similarly, other research indicated that 3 μm PS-MPs can stimulate TNF-α secretion and elevate its mRNA expression levels in RAW264.7 mouse macrophage cells [61]. Additionally, PS-NPs have been shown to activate Toll-like receptor 4 (TLR4)/p38-mediated pro-inflammatory pathways in mouse microglial cells (N9 cells) [90]. Moreover, various types of microplastic particles can also induce the production of inflammatory and oxidative stress markers in macrophages, such as monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (CXCL2), IL-6, and heme oxygenase-1 (HMOX-1) [59]. Specifically, polytetrafluoroethylene microplastics (PTFE-MPs) have been shown to increase the secretion of TNF-α and IL-6 in the U937 macrophage cell line [91]. Huang et al. [92] further found that PP-MPs at a concentration of 100 μg/mL can promote the release of TNF-α and IL-6 from mouse macrophages. While the degree of inflammation induced by microplastics varies depending on factors such as particle type, concentration, and duration of exposure, these findings collectively support the conclusion that microplastics promote M1 polarization of macrophages and exert pro-inflammatory effects.

4.3. Contradictory evidence and possible Explanations for the effects of microplastics on M1 polarization and pro-inflammatory responses in macrophages

However, many studies have reported that microplastics may have no significant effect on the polarization and activation of macrophages. For instance, Adler et al. [11] reported that exposure to PS-NPs did not result in any changes in the surface marker expression of human macrophages. Similarly, Stock et al. [93] investigated the effects of microplastics ranging from 1 to 10 μm on macrophage polarization and activation using the human cell line THP-1. Although some microplastics were absorbed by the macrophages, in vivo data revealed no histologically detectable lesions or inflammatory responses. These findings suggest that microplastics do not impact the differentiation or functional activation of human macrophage models. Interestingly, there is evidence that microplastics may inhibit M1 polarization of macrophages or even promote M2 polarization. One study examining the effects of microplastics on phagocytic dendritic cells and macrophages in vitro showed a downregulation of pro-inflammatory M1 macrophage markers [20]. Additionally, other studies indicated that exposure to PS-MPs significantly shifted the M1/M2 macrophage ratio in mouse placenta towards the M2 subtype [94]. As previously mentioned, the absorption and toxic effects of microplastics are shaped by their physicochemical characteristics and environmental conditions. This implies that the influence of microplastics on M1 polarization and pro-inflammatory responses in macrophages may similarly be affected by these factors.

The diverse surface physicochemical characteristics of microplastics can lead to either inflammatory or anti-inflammatory effects in macrophages. Research has shown that amino-functionalized polystyrene nanoparticles (PS–NH2) with diameters ranging from 1 to 100 nm, rather than carboxylated or non-functionalized particles, are capable of activating the NLRP3 inflammasome in human macrophages, promoting the release of IL-1β [95]. In contrast, another study found that carboxylated polystyrene particles measuring 500 nm and 1000 nm also triggered the release of pro-inflammatory cytokines, including IL-6 and IL-8, in monocytes and macrophages [87]. Notably, carboxylated PS-NPs demonstrated enhanced pro-inflammatory and cytotoxic effects [96]. Conversely, Fuchs et al. [97] observed that both carboxylated and amino-modified PS-NPs inhibited the polarization of macrophage to the M2 phenotype by reducing the levels of CD200R, CD163, and IL-10, without affecting M1 markers. This indicates that the effects of nanoparticles on the polarization of macrophage may depend both on the functional groups present and other physicochemical characteristics. Additionally, Huang's research group [98] found that hydrophilic polyurethane nanoparticles exhibit surface-dependent immunosuppressive properties, inhibiting M1 polarization of macrophages by decreasing TNF-α and IL-1β production. Furthermore, the surface charge of microplastics influences the formation of a protein corona, which plays a crucial role in macrophage polarization [99]. For microplastics exposed to environmental conditions and coated with an ecological corona, this effect may be further enhanced [11].

In conclusion, evaluating the effects of microplastics on macrophage polarization requires careful consideration of several factors. These include not only the variations in macrophage types used in experiments and potential experimental errors, but also the intrinsic characteristics of the microplastics themselves, such as size and surface physicochemical properties, as well as their exposure to environmental conditions.

4.4. Induction of oxidative stress by microplastics promotes cytotoxic endpoints in macrophages

In addition to the direct toxicity of microplastic particles to cell membranes and organelles, as well as the adverse effects resulting from their accumulation in lysosomes [45,52,88,100], microplastics primarily induce cytotoxic endpoints, such as inflammation, genotoxicity, and apoptosis, in macrophages through the induction of oxidative stress [91,79,101]. Most studies indicate that the production of reactive oxygen species (ROS) and the resulting oxidative stress are closely related to the harmful effects of microplastics, serving as both initiating and key molecular events in microplastic-induced toxicity [[102], [103], [104]]. ROS are a group of highly reactive molecules formed as a result of cellular oxidative metabolism. They serve as signaling molecules in various biological processes and are also the end products of many metabolic reactions, including superoxide anion (O₂•−), hydrogen peroxide (H₂O₂), and hydroxyl radicals (•OH) [105]. O₂•− is a common precursor of all ROS produced by cells and can rapidly dismutate to H₂O₂ under the catalysis of superoxide dismutase (SOD) [106,107]. While ROS help cells carry out normal physiological activities, excessive ROS can disrupt redox balance, leading to adverse effects such as oxidative stress, protein oxidation, lipid peroxidation, DNA damage, and even cell death [10,100]. Key components of the antioxidant mechanisms that protect cells from ROS-induced stress include enzymes such as glutathione peroxidase (GPX), catalase (CAT), SOD, oxidized and reduced glutathione (GSSG/GSH), and glutathione reductase (GR). Once ROS are generated within the cell, an imbalance occurs if the antioxidant mechanisms cannot compensate for oxidative stress, leading to abnormal activation of cellular signaling pathways [10].

Microplastics can stimulate ROS production through oxidative bursts and activate various cytokines [58]. Even short-term exposure to microplastics can cause a rapid increase in intracellular ROS levels, leading to membrane damage and lipid peroxidation [108]. Furthermore, the accumulation of microplastics in organs can disrupt mitochondrial function, leading to uncontrolled ROS production and the initiation of inflammatory signaling cascades and various forms of cell death [10]. Several studies suggest that ROS-induced oxidative stress is a critical factor in the cytotoxicity associated with PS-NPs [109,110].

For macrophages, the two main endogenous sources of O₂•− and H₂O₂ are the cytosolic NADPH oxidase (NOX) and mitochondria [[111], [112], [113]]. Following exposure to microplastics, macrophages rapidly internalize the ingested particles to facilitate their clearance. NOX and/or other enzymes generate O₂•− and H₂O₂ [105,114], which subsequently accumulate in the mitochondria. In this context, microplastics compromise mitochondrial integrity, leading to an increased production of mitochondrial reactive oxygen species (mtROS) [115]. Both O₂•− and H₂O₂ play roles in signal transduction and act as key mediators driving oxidative stress cascades [102].

Therefore, the ROS produced by macrophages not only play a critical role in antimicrobial defense but also regulate macrophage function by acting as important signaling molecules [116]. Microplastics can promote adverse outcomes in macrophages by enhancing ROS generation and altering metabolic characteristics [63,117,74]. Exposure to PS-NPs (500 μg/mL) induces oxidative stress in human macrophages and reduces cell proliferation [21]. PP particles smaller than 20 μm exhibit cytotoxicity to Raw 264.7 cells, with this toxicity being caused by increased ROS levels, occurring in a size- and concentration-dependent manner [118].

To further investigate the role of ROS in PS-NPs-induced necroptosis of macrophages, Fan et al. found that exposure to PS-NPs significantly downregulated the activity of the antioxidant SOD, total thiols (-SH), and GSH, while significantly upregulating the levels of the oxidative product malondialdehyde (MDA) in a dose-dependent manner. PS-NPs accumulate in the mitochondria of RAW 264.7 cells, and this accumulation leads to severe mitochondrial dysfunction, including the disturbance of complex I on the electron transport chain, membrane hyperpolarization, and ATP mutation, ultimately favoring the upregulation of mtROS to trigger necroptosis [115]. There is also evidence that ROS generated by PS-NH2 directly or indirectly affect the endoplasmic reticulum homeostasis and protein folding in macrophages, leading to endoplasmic reticulum stress and subsequent autophagic cell death [74]. PS-NPs may also induce microglial inflammatory responses and ferroptosis by promoting lipid peroxidation and ROS accumulation [119]. When exposed to NPs, the intracellular ROS levels in microglia significantly increase, while GSH and SOD levels decrease, and MDA levels rise. Pre-treatment with the ROS inhibitor N-acetylcysteine (NAC) significantly reduces the expression of MDA, while the activities of SOD and GSH are markedly increased. Furthermore, experimental results indicate that NP-induced inflammatory responses and ferroptosis are mediated by ROS. This suggests that ROS plays a critical role in the inflammation and ferroptosis of macrophages induced by microplastics [119].

Furthermore, the ROS produced by macrophages can coordinate immune responses through redox signaling in various ways, such as regulating the secretion of pro-inflammatory cytokines, activating inflammasomes, and coordinating subsequent adaptive immune responses through antigen presentation [[120], [121], [122]]. KC et al. [91] exposed six different human cell lines, including U937 and THP-1 macrophages, to two sizes of irregularly shaped PTFE-MPs with average diameters of 6.0 or 31.7 μm. They found that PTFE-MPs increased ROS levels across all tested cell lines, particularly in macrophages, and activated the ERK pathway, ultimately inducing oxidative stress and inflammation. Excessive ROS production is known to be a major contributor to the pathogenesis of inflammation and is associated with the progression of various inflammatory diseases [123]. Studies on nanoplastic-induced inflammation in macrophages have shown that nanoplastics can induce ROS production and activate the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways, leading to an upregulation of pro-inflammatory cytokines such as IL-6 and TNF-α [96]. Additionally, research has found that exposure to PS-NPs can lead to a decrease in mitochondrial membrane potential, accumulation of ROS, and calcium overload in RAW 264.7 cells. At elevated levels of ROS, this may result in mitochondrial dysfunction and the release of mitochondrial DNA (mtDNA). The free mtDNA within the cell can be recognized by cyclic GMP-AMP (cGAMP), activating the cGAS-STING signaling pathway associated with innate immunity [124]. Furthermore, PS-NPs can also induce the expression of downstream inflammatory factors, such as NF-κB, through the cGAS-STING pathway, leading to inflammation [125]. Jeon et al. [79] found a strong correlation between the intrinsic ROS-generating potential of microplastics and cytotoxic endpoints, including cytotoxicity and pro-inflammatory cytokines in THP-1 macrophages. However, some studies reported no increase in ROS production in macrophages after exposure to PS-NPs, which may be attributed to factors such as microplastic heterogeneity, concentration, exposure duration, and their effects on different tissue or cell types [11,104].

Among ROS, H₂O₂ is a promising candidate as a signaling messenger for cell death due to its relative stability, with a half-life of a few seconds. H₂O₂ easily penetrates cell membranes, allowing it to diffuse into neighboring cells and react with their components. The oxidants released by dying cells may kill adjacent cells through a bystander effect [126]. Thubagere et al. [127] found that nanoplastics can significantly impact cell viability in the CACO-2 intestinal membrane model by triggering apoptosis in individual cells, leading to oxidative stress that releases H₂O₂ into the extracellular environment and induces apoptosis in nearby cells. For macrophages, exposure to microplastics can generate substantial ROS, potentially affecting the function and health of surrounding cells through a similar bystander effect. While PS-NPs do not directly induce cytotoxicity in hepatocytes, they may upregulate ROS production and trigger redox-sensitive necroptosis in macrophages when co-cultured with RAW 264.7 cells, enhancing crosstalk between macrophages and hepatocytes and resulting in hepatocyte damage [115]. However, further evidence is needed to support the claim that microplastic exposure directly leads to increased ROS in the extracellular space of macrophages, making the exploration of microplastics’ impact on ROS levels in the macrophage microenvironment a promising direction for future research.

ROS play a pivotal role in regulating intracellular redox signaling processes, particularly targeting redox-sensitive –SH. These –SH group, being highly reactive components within proteins, are susceptible to oxidation, leading to changes in protein structure and function. When macrophages exposed to MPs, studies have observed a decrease in –SH levels, which can be attributed to the oxidative stress induced by ROS [115]. Chiu et al. found that MP-induced ROS contribute to the formation of protein misfolding aggregates, and induce endoplasmic reticulum (ER) stress. Additionally, ROS phosphorylate AMP-activated protein kinase (AMPK) and inhibit the AKT/mammalian target of rapamycin (mTOR) pathway. Both of these actions potentiate autophagic cell death [74]. During this process, ROS induce the oxidation of cysteine residues in AMPK, leading to further phosphorylation of active AMPK [128]. Furthermore, p62, a proteolytic autophagy receptor, is upregulated in response to MPs, particularly in response to H₂O₂. Under these conditions, p62 forms disulfide-linked conjugates, which contribute to the activation of autophagy [128]. The ingestion of MPs by macrophages leads to an overproduction of ROS, disrupting the cellular redox balance.

In addition to ROS, nitric oxide (NO) is another important oxidative stress signaling molecule that plays a significant role in the inflammatory responses of macrophages. Following exposure to microplastics, increases in both ROS and NO levels in vivo and in vitro contribute to oxidative stress [91]. Research has found that PS-M/NPs stimulate NO production in mouse RAW264.7 cells in a dose-dependent manner by increasing the activity of nitric oxide synthase (NOS) [61]. NO reacts with superoxide to form peroxynitrite (ONOO⁻), a potent biological oxidant that affects mitochondrial function and triggers cell death through oxidative and nitrative reactions, potentially mediating severe bystander tissue damage [129]. The upregulation of NOS and accumulation of ROS induced by microplastics create the conditions for the generation of ONOO⁻. Under light irradiation, nitrogen-containing microplastics (N-MPs) will form persistent aminoxyl radicals (PAORs) and reactive nitrogen species (RNS). Nitric oxide radicals (•NO) generated by the photolysis of nitrone groups can react simultaneously with peroxyl radicals and superoxide anion radicals (O₂•−), yielding nitrogen dioxide radicals (•NO₂) and ONOO⁻ respectively [130]. Pezzotti et al. [131] observed via specific nitrative stress-sensing dyes and high-resolution fluorescence microscopy that silicon nitride (Si₃N₄)-modified polymethylmethacrylate (PMMA) composites induce ONOO⁻ radical accumulation in Candida albicans mitochondria, indicating that Si₃N₄-endowed PMMA surface chemistry mimics macrophage antifungal mechanisms, inducing NO and O2•− to react and form candidacidal ONOO⁻. Additionally, microplastic digestive clearance generates extensive RNS. Peng et al. [132] used near-infrared spectroscopy (NIR) to quantify Tenebrio molitor biodegradation kinetics of PS-MPs and found increased ONOO⁻ levels during larval degradation of small (<30 μm) and large (<300 μm) PS-MPs, with larvae instinctively enhancing and heterogeneously redistributing intestinal ONOO⁻ in response to MP biodegradation. The formation of ONOO⁻ by macrophages represents a mechanism of cytotoxic effect that requires immune stimulation with cytokines that induce iNOS expression [133]. Additionally, exposure to nanoplastics has been shown to significantly increase the mRNA levels of iNOS in mouse microglia [90]. Taken together, these findings suggest that NO may serve as an additional mechanism through which microplastics exert pro-inflammatory effects on macrophages. It links the NOS-mediated generation of NO, the accumulation of ROS, and the ONOO⁻-related oxidative/nitrative stress.

4.5. The impact of microplastics on macrophages through gut microbiota

Besides the direct pathological and physiological effects of microplastics, it is important to highlight that many environmental microplastics contain additives. These additives can promote the adhesion and growth of bacterial pathogens on or within the particles, transforming microplastics into potential carriers of microbial toxicity. This raises concerns about the further toxic effects that may occur when these particles cross human biological barriers [1,18]. Microplastics can act as a Trojan horse for foreign pathogens, adversely affecting the resident microbiota of organisms and leading to dysbiosis in the gut, nose, and lungs [134,135]. For instance, Multiple studies have demonstrated that long-term exposure to microplastics in mice leads to dysbiosis, impaired intestinal barrier function, and metabolic disorders [18,136]. Environmental microplastics tend to enrich opportunistic pathogens decreasing the abundance of beneficial bacteria [137]. The relationship between gut probiotics and intestinal barrier integrity underscores that dysbiosis plays a significant indirect role in microplastic-induced intestinal dysfunction [138,139].

Furthermore, dysbiosis and intestinal dysfunction induced by microplastics can have widespread systemic effects on various host systems, including the digestive, immune, hematopoietic, nervous, and reproductive systems [18,[140], [141], [142], [143], [144]]. Studies have demonstrated that PS-MPs disrupt the gut microbiome, compromise the intestinal barrier, increase peripheral inflammation, and alter serum metabolites profiles. Additionally, Lipopolysaccharides (LPS) resulting from dysbiosis can activate macrophage TLR4, leading to the expression of hypoxia-inducible factor 1-alpha (HIF-1α). This activation initiates aerobic glycolysis, which enhances ATP production and promotes a pro-inflammatory phenotype in macrophages [145]. Importantly, research indicates that addressing the dysbiotic gut microbiome caused by PS-MPs can significantly reduce serum concentrations of LPS, IL-1β, IL-6, and TNF-α. This reduction may help prevent intestinal barrier damage and peripheral inflammation induced by PS-MPs. Furthermore, such interventions can inhibit the TLR4/MyD88/NF-κB pathway and thereby reducing neuroinflammation [137].

As previously mentioned, the innate immune system serves as the first line of defense against microbial and microplastic pollution, with macrophages playing a critical role in this response. Acting as gatekeepers, macrophages directly interact with microplastics, microorganisms, and their metabolic byproducts, effectively capturing and eliminating these “criminals” or “hit-and-run offenders”. Moreover, macrophages can mount an immune response to the metabolic products resulting from the interaction between microplastics and microorganisms. They adapt to changes in the microenvironment by expressing various functional programs tailored to the specific challenges they encounter. Therefore, long-term exposure to microplastics can lead to dysbiosis and metabolic disorders, which may adversely affect the functional activities of macrophages (Fig. 3). This disruption underscores the importance of further investigation into the effects of microplastic exposure on innate immunity and overall health.

Fig. 3.

Microplastics indirectly affect macrophages by disrupting gut microbiota. Microplastics disrupt gut microbiota and increase intestinal permeability, facilitating the entry of bacteria and their metabolites into the body. This dysbiosis leads to LPS activation of macrophage TLR4, inducing HIF-1α expression, which triggers aerobic glycolysis and promotes a pro-inflammatory macrophage phenotype. Additionally, it activates the TLR4/NF-κB signaling pathway, leading to the release of inflammatory cytokines.

5. Macrophages: A key intersection in microplastic-induced tissue and organ toxicity

Microplastics are pervasive in the environment, and humans inevitably encounter them through air, food, water, and daily interactions. Macrophages serve as a crucial first line of defense against foreign pathogens, being key in both preventing and clearing these threats. Additionally, since macrophages are integral to the inflammatory response, any dysfunction in their function can lead to widespread inflammatory damage in various organ tissues. However, the potential for microplastics to induce diseases, either directly or indirectly, through macrophage involvement is complex and multifaceted [93,146] (Fig. 4). The following discussion will explore the organ toxicity associated with microplastics mediated by macrophages, as summarized in Table 2.

Fig. 4.

Macrophages play a central role in mediating tissue toxicity induced by microplastics. A. Intestinal toxicity; B. Hepatotoxicity; C. Arterial toxicity; D. Reproductive toxicity; E. Pulmonary toxicity; F. Neurotoxicity.

Table 2.

Microplastic-induced organ toxicity mediated by macrophages.

Microplastic Type and Size	In Vivo and In Vitro Models	Administration Method/Dose	Disease	Possible Mechanism	References
PS (1–10 μm and 50–100 μm)	In Vivo: 6-week-old C57BL/6 mice In Vitro: Mouse mononuclear macrophage RAW264.7	Continuous oral administration was conducted for 35 days, with daily doses ranging from 0.6 to 0.7 μg, 6–7 μg, and 60–70 μg	Hepatotoxicity	PS-MP induces the formation of macrophage extracellular traps and contributes to liver fibrosis through the activation of the ROS/TGF-β/Smad2/3 signaling axis.	[147]
PS (<15 μm)	In Vivo: C57BL/6 mice In Vitro: Mouse Kupffer cells	Continuous intravenous injection was administered for 28 days at a dose of 10 mg/kg per day	Hepatotoxicity	PS-MP exacerbates acute liver injury by promoting Kupffer cell pyroptosis.	[148]
PS (5 μm)	In Vivo: 1-week-old chicks In Vitro: Chicken liver macrophages	Continuous oral administration was performed for 42 days, with daily doses of 0, 1 mg/L, 10 mg/L, and 100 mg/L	Hepatotoxicity	PS-MP induces reactive oxygen species and damages mitochondria, leading to autophagy and lysosomal disruption, which results in the formation of extracellular traps and promotes liver inflammation.	[149]
PS (0.5 μm)	In Vivo: 8-10-week-old male C57BL/6J mice	Continuous oral administration was conducted for 28 days, with a daily dose of 0.5 mg in 100 μL	Hepatotoxicity	PS-NP enhances inflammation in mouse liver tissue through macrophage polarization and the infiltration of natural killer cells.	[89]
PS (50 nm)	In Vivo: 1-2-month-old ApoE−/− mice In Vitro: Mouse mononuclear macrophage RAW264.7	Continuous oral administration was carried out for 19 weeks, with doses of 2.5, 25, and 250 mg/kg	Atherosclerosis	PS-NP activates phagocytosis in M1 macrophages within the aorta, promoting the upregulation of the scavenger receptor, which exacerbates arterial stiffness and contributes to atherosclerotic plaque formation.	[150]
PS (100 nm)	In Vivo: 6-8-week-old male ApoE−/− mice In Vitro: Mouse mononuclear macrophage RAW264.7	Administration was conducted twice a week for 3 months, with doses of 5 and 10 mg/kg per dose	Atherosclerosis	PS-NP induces lipid accumulation in macrophages, resulting in cellular oxidative stress and inflammation, which in turn triggers atherosclerotic disease.	[151]
Sulfate-modified PS-NP (S-NPs) (200 nm)	In Vitro: Mouse mononuclear macrophage RAW264.7 and human monocyte THP-1	Cells were treated with concentrations ranging from 5 to 500 μg/mL	Atherosclerosis	S-NPs stimulate the accumulation of lipid droplets in the cytoplasm, resulting in the differentiation of macrophages into foam cells.	[22]
PS (0.2 μm/2 μm/10 μm)	In Vivo: 8-week-old C57BL/6 mice In Vitro: Human microglial cells HMC-3	Continuous oral administration was performed for 7 days, with a daily volume of 200 μL containing concentrations of 0, 2.5, and 10 μg/mL	Atherosclerosis	The uptake of PS-MP induces immune activation in microglial cells, ultimately resulting in cell apoptosis.	[70]
PS (50 nm)	In Vivo: 8-week-old male C57BL/6J mice In Vitro: Mouse BV2 cells	Continuous oral administration was carried out for 7 days, with dosages of 0.5, 2.5, 10, and 50 mg/kg	Neurotoxicity	PS-NP accumulates in mouse brain tissue, triggering microglial activation and leading to neuronal damage.	[152]
PS (2.5 μm)	In Vivo: C57BL/6J mice In Vitro: Mouse microglial cells BV2 and mononuclear macrophage RAW264.7	Tail vein injections were administered once every 3 days for a total of 28 days, with doses of 1, 10, and 100 mg/kg per injection	Neurotoxicity	PS-MP exacerbates neuroinflammation by inducing microglial pyroptosis, which in turn promotes cognitive impairment in Alzheimer's disease.	[153]
PE (∼500 nm/∼2 μm)	In Vivo: BALB/c mice (6 months old), APP-PS1 mice (6 months old, half male and half female), and ICR mice In Vitro: Mouse mononuclear macrophage RAW264.7	Continuous oral administration was conducted for a duration ranging from one week to two months, with a daily dosage of 10 mg/kg	Neurotoxicity	NP influences brain immunity by inducing microglial activation and Th17 differentiation through IL-1 signaling in intestinal macrophages.	[7]
Weathered PS-MP (100 μm)	In Vivo: 6-week-old male C57BL/6 mice In Vitro: Human microglial cells HMC-3	Continuous oral administration was performed for 7 days, with a daily dosage of 2 μg in 100 μL	Neurotoxicity	Weathered microplastics induce brain toxicity by promoting M1 polarization of macrophages.	[154]
PS (50 nm)	In Vitro: Mouse microglial cells BV2	Cells were treated for either 12 or 24 h with concentrations of 0, 25, 50, or 100 μg/mL	Neurotoxicity	Microplastics induce ferroptosis in microglial cells by modulating JNK/HO-1/FTH1 signaling.	[119]
PS (80 nm)	In Vivo: 8-week-old male C57BL/6 mice In Vitro: Mouse macrophage RAW264.7 and mouse spermatocyte-derived GC-2spd(ts) (GC2)	Continuous oral administration was conducted for 4 weeks, with daily dosages of 0.1 mg, 0.25 mg, and 0.5 mg	Reproductive toxicity	Macrophage polarization occurs in a ROS-dependent manner, activating the ROS-macrophage migration inhibitory factor/NF-κB signaling pathway, which subsequently induces apoptosis in GC2 cells.	[155]
Mixture of MNPs (25–30 nm, 1–5 μm, 20–27 μm, and 125–150 μm)	In Vivo: 8-week-old male C57BL/6 mice	Continuous oral administration was carried out for 21 days, with a daily dosage of 0.1 mg	Reproductive toxicity	MNPs ranging from 1 to 5 μm invade testicular macrophages, inducing testicular inflammation through the modulation of these macrophages	[156]
PS (100 nm)	In Vivo: 5-6-week-old male SD rats In Vitro: THP-1 cells	Continuous nasal feeding was conducted for 90 days, with daily exposure levels of 0, 0.5, 1.0, or 2.0 mg/m3	Pulmonary toxicity	Exposure to PS-MP results in increased expression of MMP9 and MMP12 in macrophages, which contributes to the degradation of elastin, thereby exacerbating emphysema	[157]
PS (1–5 μm)	In Vivo: 6-8-week-old female BALB/c mice In Vitro: THP-1 cells	Nasal administration was performed every three days for a total of 24 days, with each dose consisting of 300 μg of MP in 20 μL of saline	Pulmonary toxicity	PS-MP causes significant macrophage aggregation, leading to increased mucus secretion and inflammatory cell infiltration, thereby exacerbating asthma symptoms.	[85]
Polyamide (PA) (8.13 ± 2.27 μm)	In Vivo: Zebrafish larvae	Exposed to a PA solution for 3 days, with the solution being changed every 24 h at concentrations of 5, 20, and 50 mg/L	Developmental toxicity	PA-MP inhibits larval development through macrophage-mediated pro-inflammatory responses and apoptosis.	[158]

5.1. Intestinal toxicity

The gastrointestinal tract is the main site for the accumulation and toxic effects of ingested microplastics. When microplastics accumulate in the intestine, they can cause various negative effects, such as reduced secretion of intestinal mucins, impaired intestinal barrier function, gut microbiota dysbiosis, and activation of mucosal immunity and inflammation [18,[159], [160], [161], [162], [163], [164], [165]]. Increasing evidence suggest that the rising global incidence of inflammatory bowel disease (IBD) may be linked to the growing prevalence of microplastic particles in the environment [166]. For instance, Yan et al. [167] found that individuals with IBD had significantly higher concentrations of microplastic particles in their feces compared to healthy individuals, and that the concentration of microplastics was positively correlated with the severity of IBD. Additionally, microplastics can disrupt colonic epithelial homeostasis, contributing to intestinal overgrowth and exacerbating the severity of colitis [168]. Studies have shown that oral administration of PP-MPs can disrupt oxidative stress balance and activate the TLR4/NF-κB signaling pathway in mouse intestines, leading to colonic apoptosis and damage to the intestinal barrier [161].

Macrophages are essential in mediating tissue tolerance under both homeostatic and inflammatory conditions [169]. As key regulators of intestinal immune balance, they can exhibit different functional phenotypes in response to different environmental signals and stimuli, significantly influencing the promotion or resolution of intestinal inflammation [170,171]. Their ability to sense the intestinal environment during homeostasis, combined with their innate capacity to drive excessive inflammatory responses during intestinal diseases, places intestinal macrophages at a critical junction between protective immunity and inflammation [172]. Microplastics can induce inflammatory responses particularly by activating macrophages and inducing the production of relevant cytokines. Prolonged exposure to microplastics in the intestines of mice has been shown to significantly upregulate the innate immune receptor protein TLR-4 and interferon regulatory factor 5 (IRF5), thereby activating the innate immune system [173]. Furthermore, exposure to microplastics has been observed to increase the proportion of M1 macrophages while decreasing the proportion of M2 macrophages in the intestines of adult zebrafish [88]. Additionally, microplastics not only induce inflammatory damage in the colons of mice but also trigger macrophage reprogramming to produce intestinal IL-1β through lysosomal damage. This process leads to the differentiation of Treg and Th17 cells, which is linked to T cell exhaustion in the colon, creating a colonic environment conducive to tumor initiation and progression [7,174]. Moreover, microplastics can amplify inflammation by activating the very late antigen 4-vascular cell adhesion molecule 1 (VLA4-VCAM1) signaling pathway in macrophages, which promotes the generation of ROS [175]. As previously mentioned, prolonged exposure to microplastics can lead to gut microbiota imbalance and metabolic disorders. Intestinal-resident macrophages are essential for controlling gut fungi and bacteria, as they integrate signals from the luminal microbiota to maintain intestinal homeostasis and act as key cellular sensors [172]. Therefore, microplastics may also influence the development of intestinal inflammation by inducing dysbiosis and metabolic disturbances in the gut [173,176].

5.2. Hepatotoxicity

The liver is among the first organs to process environmentally harmful substances absorbed through the intestine and serves as the largest metabolic organ, playing a crucial role in the metabolism of microplastics in the body [147,177]. Microplastics that are consumed or those that escape the digestive system can directly access the liver via the portal vein [149]. Once in the liver, they can accumulate and cause pathological changes, leading to liver damage [177,178]. For instance, the widely used microplastic PMMA has been shown to induce hepatotoxicity through the elevation of inflammatory markers and the induction of oxidative stress [3].

Macrophages are the primary immune cells in the liver, including both the resident Kupffer cells and the infiltrating macrophages from the bone marrow. These liver macrophages exhibit significant heterogeneity and are crucial in liver diseases [179], making them potential targets for influencing the development and resolution of fibrosis [180]. Microplastics can increase macrophage infiltration in the mouse liver and stimulate macrophage polarization, leading to inflammation characterized by an upregulation of M1 macrophages and a downregulation of M2 macrophages [89]. PS-MPs can promote liver inflammation by stimulating macrophages to form extracellular trap structures (ET) with inflammatory characteristics [149]. The macrophage ET induced by PS-MP can also lead to liver fibrosis by activating the ROS/transforming growth factor beta (TGF-β)/SMAD Family Member 2/3(Smad2/3) signaling pathway [147]. Furthermore, prolonged exposure to PS-MPs can promote pyroptosis in Kupffer cells, thereby exacerbating acute liver injury [148].

The liver is a primary target organ for exogenous stimuli, and its normal function is closely linked to a bidirectional communication with the gut microbiota [181]. The connection between gut and liver diseases, along with the interactions among the gut, liver, and microbiota, is conceptualized as the “gut-liver axis”. The gut-liver axis plays a significant role in the hepatotoxicity induced by microplastic exposure. On one hand, microplastics can disrupt or breach the intestinal barrier, enabling them to reach the bloodstream and subsequently translocate and invade the liver, causing hepatotoxicity. On the other hand, microplastics can directly damage the ecological structure of the intestine, allowing harmful bacteria and metabolic products to breach the intestinal barrier and reach the liver through the gut-liver axis, thereby inducing liver damage [141]. Studies have shown that microplastics can disrupt the homeostasis of the gut microbiome, leading to hepatocyte injury and functional impairment by activating the TLR2/NF-κB/NLRP3 pathway in the liver [182]. Additionally, PS-MPs can modify the gut microbiota composition in mice and induce hepatic lipid dysregulation [183]. Importantly, Wen et al. [184] observed that microplastics disrupt gut microbial balance, which exacerbates liver injury induced by cyclophosphamide (CTX). Further experiments involving fecal microbiota transplantation (FMT) demonstrated that the dysbiosis of gut bacteria induced by microplastics is crucial in increasing the liver's sensitivity to CTX stimulation. PS-NPs promote macrophage infiltration in the intestine and weaken the intestinal barrier, leading to the release of LPS. This, in turn, triggers liver inflammation and induces pyroptosis in hepatocytes through activation of the TLR4/NF-κB/Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3(NLRP3)/Gasdermin D (GSDMD) signaling pathway [185]. This suggests that liver injury in mice is primarily driven by dysfunction of the gut-liver axis.

5.3. Arterial toxicity

Once microplastics enter the circulatory system, they can flow through the blood and redistribute to various organs. A study has shown that micro/nanoplastics composed of PET, PS, or PE are present in human blood, with an average of 1.6 μg of plastic particles per ml of blood sample [186]. However, microplastics may also accumulate in the arteries that circulate blood throughout the body, potentially leading to inflammatory diseases of the arteries. Vlacil et al. [187] were the first to demonstrate that PS particles can activate endothelial cells, which subsequently adhere to monocytes. This process plays a crucial role in the immune response and also marks the onset of atherosclerosis. Atherosclerosis is a long-term inflammatory condition that impacts medium and large arteries, marked by the buildup of macrophages rich in cholesterol and lipids, known as “foam cells” [188,189].

Macrophages are essential to the progression of atherosclerosis [190], and pathological processes associated with them are viewed as key targets for diagnostic imaging and novel therapies for the condition [150]. Microplastics are emerging as potential risk factors for atherosclerosis, with mechanisms involving the induction of lipid accumulation in macrophages and their differentiation into foam cells. Exposure to PS-NPs can disrupt genes involved in lipid influx and efflux in macrophages, leading to intracellular lipid buildup. This causes oxidative stress and inflammation, which may contribute to the development of atherosclerosis [150,151]. Beyond PS-NPs, studies have highlighted substantial morphological and lipid metabolic changes in human M1 macrophages exposed to PP-NPs and PVC-NPs at concentrations of 20 μg/ml [78]. Additionally, exposure to PS-NPs stabilized by anionic surfactants has been shown to strongly stimulate lipid metabolic dysregulation and foam cell formation. Sulfate-modified PS-NPs can trigger intracellular lipid buildup, causing macrophages to transform into foam cells, a hallmark of atherosclerosis pathogenesis [22,191].

In addition to findings from mammalian experiments and in vitro macrophage studies suggesting that microplastics may promote atherosclerosis, there is corresponding clinical evidence involving human atherosclerosis. Wu et al. [192] provided the first images and μRaman spectra of microparticles in human arterial thrombi, revealing a significant accumulation of insoluble particles, including synthetic material microparticles, in the arteries. In a preclinical study, researchers analyzed microplastic in carotid plaque samples taken from 257 patients, finding polyethylene in the plaques of 150 patients (58.4 %), with an average concentration of 21.7 ± 24.5 μg/mg of plaque. Electron microscopy identified distinct serrated foreign particles in plaque macrophages, interspersed with external debris [193]. Liu et al. [194] detected microplastics in three different human artery types using pyrolysis gas chromatography/mass spectrometry (Py-GC/MS): coronary and carotid arteries with atherosclerotic plaques, as well as aorta free of plaques. Microplastics were detected in all 17 arterial samples, with an average tissue concentration of 118.66 ± 53.87 μg/g. Notably, microplastic levels in the coronary and carotid arteries was notably higher compared to that in the aorta without atherosclerotic plaques, suggesting a potential association between microplastics and human atherosclerosis. Furthermore, an increasing number of studies indicate that gut microbiota and related metabolites are associated with the occurrence, prevention, treatment, and prognosis of atherosclerosis [195,196]. Thus, the lipid oxidation and inflammatory signals generated by microplastics through disruption of gut ecology may also contribute to atherosclerosis, although specific evidence is still lacking and further research is needed to support this hypothesis.

5.4. Reproductive toxicity

Microplastics in circulation can disrupt the stability of the blood-testis barrier and accumulate in the testes [[197], [198], [199]]. This accumulation induces oxidative stress, affecting the regulation of genes involved in apoptosis and inflammatory responses, ultimately leading to damage to the microstructure and function of the testes [[155], [200], [201], [202]]. Testicular macrophages, which are the predominant immune cells found in the testes, serve as guardians of fertility. They not only maintain testicular immune homeostasis but also serve an essential function in regulating testosterone production and spermatogenesis [203]. An appropriate balance between M1 and M2 macrophage polarization is essential for maintaining spermatogenesis. An increase of M1-like macrophages is associated with infertility, testicular atrophy, and a decrease in viable sperm [204].

Studies have found that exposure to PS-NPs results in significant vacuolization within the seminiferous tubules, possibly caused by the infiltration of M1 macrophages. PS-NPs can trigger an M1 polarized phenotype, activating the ROS-macrophage migration inhibitory factor (MIF)/NF-κB signaling pathway, which induces apoptosis in GC-2spd(ts) cells (derived from spermatogonia) in a co-culture models with macrophages [155]. Macrophages also have secretory functions. They interact closely with testicular interstitial cells and release various cytokines to facilitate the regulation of testosterone synthesis [205]. Disruption of the polarization balance of macrophages adversely affects testosterone synthesis and secretion. Exposure to PS-MPs leads to the proliferation of macrophage and their polarization toward the M1 phenotype. Furthermore, the presence of PS-MPs triggers macrophages to release TNF-α, activating the NF-κB signaling pathway in interstitial cells, ultimately inhibiting testosterone synthesis and secretion [206].

The harmful effects of microplastics extend beyond male reproduction. They have also been shown to exhibit reproductive toxicity in females [207]. As an example, exposure to PS-MPs increases IL-6 levels in mouse ovaries while decreasing malondialdehyde (MDA) levels [208]. Furthermore, microplastics have the ability to traverse the placental barrier, potentially impacting maternal-fetal health at various levels [209]. The polarization balance of macrophages at the maternal-fetal interface is crucial for maintaining a healthy pregnancy [210]. Macrophage polarization is influenced by the local tissue microenvironment. Therefore, exposure to microplastics can disrupt maternal-fetal immune balance, particularly the polarization balance of macrophages, leading to pregnancy-related toxicity. Research has indicated that in allogeneic mating mouse models, exposure to PS-MPs results in fetal loss because of alterations in the immune microenvironment. This disruption is characterized by a reduction in the quantity and size of uterine small arteries, a decrease in decidual NK cells, a reversal of the M1/M2 cell ratio, and alterations in pro-inflammatory and anti-inflammatory cytokine secretion [94].

5.5. Neurotoxicity

Microplastics that enter the bloodstream inevitably encounter the blood-brain barrier. Microplastics in the blood can directly disrupt the integrity of the blood-brain barrier. Additionally, persistent peripheral inflammation or metabolic products resulting from gut dysbiosis and the deterioration of the intestinal barrier caused by microplastics can damage the blood-brain barrier through the gut-brain axis [143,211]. Moreover, small-sized microplastics have the ability to cross the blood-brain barrier and accumulate within the brain [[152], [212], [213]], causing a range of neurotoxic effects [[214], [215], [216], [217], [218], [219]].

After seven days of daily PS-MP oral treatment in mice, Kwon et al. [70] detected accumulation of microplastics in the cerebral cortex, hippocampus, and cerebellum, particularly in the brain's microglia. Microglia serve as the brain's macrophages and are the main resident immune cells in the central nervous system, acting as the first responders to foreign substances that may evade the blood-brain barrier [220]. They are essential for detecting and clearing microplastics in the brain and initiating inflammatory immune responses in the presence of microplastics. Microglia exhibit a significant and active response to microplastics found in the brain, so the neurotoxicity caused by microplastics crossing the blood-brain barrier may be mediated through the activation of microglia [152]. In human microglia treated with PS-MPs and in mouse brains, changes in the expression of microglial differentiation markers were observed, alongside the activation of NF-κB, pro-inflammatory cytokines, and apoptosis markers [70]. Furthermore, Shan et al. [152] found that PS-NPs significantly increased blood-brain barrier permeability and accumulated in the mouse brain in a dose-dependent way. Importantly, exposure to PS-NPs induced the stimulation of BV2 microglial cells, resulting in noticeable cell body enlargement, excessive ROS production, and increased secretion of TNF-α and IL-1β. Additionally, the conditioned medium from BV2 cells exposed to PS-NPs caused significant damage to mouse neuronal HT-22 cells.

Microplastics can also induce gut dysbiosis, leading to neuronal damage by interfering with the microbiome-gut-brain axis [143,221,222]. Gut dysbiosis can increase intestinal permeability, precede changes in central nervous system immunity and trigger neuroinflammation [223]. The activation of microglia and the resulting immune alterations can also arise as a secondary effect to microplastic-induced gut dysbiosis [143]. Microplastics can trigger inflammatory signals in gut macrophages, leading to adverse effects on the nervous system through the gut-brain axis. Yang et al. [7] found that nanoplastics can induce lysosomal damage, triggering macrophage reprogramming to produce intestinal IL-1β. Furthermore, signaling of IL-1β originating from the gut can impact brain immune responses, causing activation of microglia and differentiation of Th17 cells, which may ultimately contribute to cognitive decline and impairments in short-term memory in mice [7].

5.6. Pulmonary toxicity

Various types and shapes of microplastics have been detected in human lung tissues [224,225]. After inhalation, microplastics navigate from the nasal cavity through the respiratory tract to reach the alveoli, where gas exchange occurs in the lungs. Although nasal hairs can block larger particles, and mucus cilia can trap them for clearance through coughing or phlegm, some microplastics may accumulate deep in the lungs or even enter the bloodstream. Particles exceeding than 10 μm usually get trapped in the upper respiratory tract, while those smaller than 10 μm are capable of reaching the bronchioles. Additionally, particles smaller than 2.5 μm, including ultrafine particles, can infiltrate the alveoli [226].

Microplastics can disrupt the biophysical functions of lung surfactants and compromise the structural integrity of the alveoli and the barrier function of the airways. Additionally, microplastics that settle deep within the respiratory tract can trigger localized pro-inflammatory responses facilitated by macrophages or epithelial cells. This leads to the generation of ROS, release of inflammatory mediators, and apoptosis, contributing to both acute and chronic respiratory diseases [[227], [228], [229], [230], [231]]. Studies have shown that PS-MPs can induce cytotoxicity and inflammation in human lung epithelial cells by production the formation of ROS [228]. The activation of the TLR4 pathway, along with NF-κB, and the NLRP3 inflammasome, has been linked to PS-MP-induced lung inflammation [232]. Furthermore, NPs trigger mitochondrial damage, ROS-induced oxidative stress, apoptosis, necrosis, and inflammation while activating the cGAS-STING signaling pathway, resulting in notable pulmonary fibrosis [124,233].

Moreover, a significant portion of microplastics inhaled through the respiratory tract has been detected in extrapulmonary tissues, including blood, bone marrow, liver, brain, heart, spleen, and kidneys. This indicates that microplastics may transfer from the alveoli to these extrapulmonary organs via endocytosis by alveolar macrophages into the bloodstream [227]. Macrophages located on the epithelial surface of the lungs serve as a crucial first line of defense, as they are immersed in the surface lining layer and directly exposed to environmental pathogens [234]. They play essential roles in maintaining lung homeostasis, clearing pathogens, and regulating immune responses, significantly influencing both acute and chronic lung diseases [235].

Consequently, microplastics can directly induce a range of pulmonary toxicity symptoms through their interaction with macrophages. Lu et al. [85] found that inhaling microplastics in normal mice led to the infiltration of inflammatory cells in the lungs, especially macrophages aggregation, elevated TNF-α levels in alveolar lavage fluid, and increased IgG1 production. In mice with asthma, microplastics inhalation resulted in more macrophage aggregation, heightened mucus production, and worsened asthma symptoms due to greater inflammatory cell infiltration. Furthermore, exposure to PS-MPs can alter the extracellular matrix (ECM) composition in macrophages, leading to ECM degradation and worsening emphysema [157].

6. Therapies targeting microplastic-macrophage axis and microplastic-gut microbiota-macrophage axis-induced diseases

6.1. Targeted Macrophage therapies to mitigate the adverse effects induced by microplastics

Microplastics pose significant hazards to different organs and tissues and may also contribute to the onset of various inflammatory diseases. Microplastics can even influence cancer progression by altering the tumor microenvironment and impairing immune surveillance, thereby promoting tumorigenesis and metastasis [236]. Studies have shown that cancer-specific proteins can enhance the phagocytosis of nanoparticles by human macrophages, leading to a strong pro-inflammatory response that contributes to tumor promotion [75]. Furthermore, the long-term chronic inflammation induced by microplastics in vivo can significantly alter the tumor microenvironment, where macrophages in the inflammatory milieu may promote the growth and survival of tumor cells by secreting growth factors and cytokines [237]. However, further evidence is needed to elucidate the exact mechanisms by which microplastics affect the direct involvement of macrophages in tumor development. The potential toxicity of microplastics primarily stems from oxidative stress and inflammatory responses that occur following exposure and ingestion [238,55]. As the primary line of defense against pathogen invasion, macrophages are essential in initiating immune responses and are actively engaged in the absorption, distribution, and clearance of microplastics within the body. Consequently, therapies that target macrophages may effectively mitigate the health risks linked to microplastics.

Research has demonstrated the use of nanotechnology aimed at macrophages in the diagnosis and treatment of atherosclerosis [239]. By employing targeted nanoparticles, researchers can deliver anti-inflammatory drugs or regulatory factors directly to macrophages, thereby reducing the inflammatory responses triggered by microplastics. Moreover, studies suggest that functionalized nanoparticles can shift macrophage polarization from M1 to M2, which is essential for restoring immune balance in patients with cancer or chronic inflammation [97]. Thus, using functionalized nanoparticles to shift macrophages from the M1 to the M2 polarization state can promote tissue repair and restore immune equilibrium. This reprogramming not only enhances the ability of macrophages to clear microplastics but also decreases the risk of chronic inflammation and tissue damage associated with microplastics.

In summary, targeting macrophages, the first line of defense against microplastics, emerges as a promising therapeutic strategy in precision medicine. On one hand, various macrophage-associated biomarkers can serve as key diagnostic tools for disease identification; on the other hand, multiple proteins related to macrophages can become effective targets for precision treatments of various diseases.

6.2. Targeting the gut microbiota-macrophage axis for treating microplastic-induced diseases

Research has demonstrated that microplastics can disrupt gut ecology, while the gut microbiota can influence the degradation of these microplastics. Different microorganisms, including bacteria, fungi, bacterial consortia, and biofilms, found in various ecological environments possess the capability to degrade different forms of microplastics [240,241]. Additionally, certain microorganisms present within the body have been reported to contribute to this degradation process [242]. The gut microbiota facilitates microplastics breakdown through enzymatic catalytic processes, such as biodeterioration, fragmentation, assimilation, and mineralization [243,244]. During these processes, microplastics gradually decompose into small molecular oxidation metabolites such as carbon dioxide, water, methane, and nitrogen [245]. Therefore, introducing specific microbial communities can improve the breakdown of microplastics, thereby mitigating their disruptive impacts on the gut microbiome.

Importantly, the presence of microplastics can induce dysbiosis and metabolic disorders within the gut microbiota, leading to alterations in macrophage metabolic functions. These changes may trigger a cascade of organ and tissue damage associated with macrophage dysfunction. Consequently, modulating the gut ecosystem and inhibiting the pro-inflammatory properties of macrophages may effectively reduce the risk of organ damage induced by microplastics. Xu et al. [246] found that resveratrol could alleviate colitis in mice by enhancing the composition and diversity of the microbiota, as well as reducing metabolic disorders. This effect is closely linked to macrophage polarization mediated by arginine metabolism, highlighting the microbiota-macrophage-arginine metabolism axis as a potential target for treating intestinal inflammation. Furthermore, research by Jia et al. [247] indicated that the potential probiotic Lactobacillus johnsonii could activate macrophages and stimulate the release of IL-10 through the TLR1/2-STAT3 pathway, thereby alleviating experimental colitis. Additionally, studies by You et al. [248] revealed that treating human peripheral blood mononuclear cells (PBMCs) with Lactobacillus fermentum strains KBL374 or KBL375 reduced levels of inflammatory cytokines IL-2, interferon-γ (ΙFΝγ), IL-4, IL-13, and IL-17A, while increasing levels of the anti-inflammatory cytokine IL-10. In mouse models, administration of these strains reshaped and increased the variety of the gut microbiota, particularly enhancing the prevalence of beneficial microorganisms such as Lactobacillus and Akkermansia spp.

In summary, probiotics have a significant impact not only on addressing microplastic-induced gut dysbiosis but also as immunomodulators and anti-inflammatory agents targeting macrophage-related therapies for intestinal inflammation. Therefore, targeting the gut microbiota-macrophage axis presents a promising treatment strategy for both clearing microplastics from the body and improving macrophage function, ultimately reducing the risk of chronic inflammation and tissue damage associated with microplastics. This approach offers novel perspectives on the prevention and treatment of microplastic-induced diseases, holding significant potential for clinical applications.

7. Future perspectives and conclusions

Despite the widespread recognition of human exposure to microplastics and their accumulation in the body, the fate of microplastics within human organ systems remains a topic of ongoing debate. This controversy primarily stems from the unclear health impacts of microplastics that are ingested through various routes, including inhalation, food consumption, nutrient transfer, or skin contact. Additionally, significant differences exist between microplastics found in nature and those synthesized in laboratories, particularly regarding their chemical characteristics such as size, shape, surface charge, and concentration. These variations complicate the assessment of their toxicity (Table 3). The complexity of this issue is further heightened by differences in human physiology across various age groups and health conditions, as well as the intricate metabolic processes involved. Current experimental techniques and methodologies are still inadequate, resulting in substantial knowledge gaps concerning whether and how microplastics may trigger health hazards through macrophages.

Table 3.

Limitations of research on the potential hazards of microplastics to humans.

Significant Differences in Toxicological Properties of Different Microplastics	Factors such as particle size, shape, surface charge, concentration, environmental exposure, and interactions with other chemical pollutants can all influence the toxic effects of microplastics.
Inadequate Experimental Techniques and Methods for Assessing Microplastic Toxicity	Measurement techniques for parameters such as size, shape, and surface charge still require further refinement. The current resolution is often too low, which may lead to the omission of many small particles.
Challenges with Control Groups	It is difficult to find organisms that are free of microplastics, as almost all organisms may be affected by them. For instance, during cell culture processes, cells may be exposed to different types of plastics. Additionally, mice drinking water from plastic bottles may also influence experimental results.
Complex Human Metabolism	Sensitivity to microplastics and immune status can vary significantly among individuals of different ages and physiological or pathological conditions. (It is challenging to simulate this in experimental animals.)

To address these potential health risks, it is crucial to conduct further in vivo and in vitro studies while also strengthening environmental management and public health education [249]. Reducing exposure and contact pathways is crucial for lowering risks associated with microplastics. Governments should promote effective management strategies, implement recycling policies, and foster the development of innovative technologies. This includes creating environmentally friendly materials to replace synthetic polymers, improving waste management systems, and utilizing advanced filtration technologies and detoxification methods for plastic waste [10,29]. Moreover, comprehensive risk assessments are necessary [37,250]. Establishing standardized methods for the characterization, detection, and toxicological study of microplastics will be vital. Developing effective technologies for accurately identifying, quantifying, and dynamically tracking microplastics and their intracellular localization within biological systems is also important. Integrating multi-omics analyses with toxicity studies can help identify highly specific and sensitive biomarkers in both in vivo and in vitro samples. Additionally, there is a need to focus on developing targeted therapeutics aimed at the microplastic-macrophage axis and the microplastic-gut microbiota-macrophage axis.

Most existing studies have linked microplastic exposure to various biomarkers of cytotoxicity, such as inflammation, oxidative stress, genotoxicity, and apoptosis, while exploring the potential hazards across different organ systems. However, evidence regarding specific cellular mechanisms and key genes or molecular pathways remains insufficient, and significant gaps exist in both in vivo and in vitro research, sometimes yielding contradictory results. This review presents new perspectives and interpretations of the potential hazards associated with human exposure to microplastics based on existing evidence, bridging organ boundaries and scientific silos. It discusses effective targeting of pathogenic modules, providing important perspectives for the prevention, assessment, and treatment of microplastic-related harms.

CRediT authorship contribution statement

Yinxing Cui: Writing – review & editing, Writing – original draft, Visualization, Data curation. Yuqi Wu: Writing – original draft, Visualization, Data curation. Pan Shi: Data curation. Yan Ni: Visualization, Conceptualization. Huaying Zeng: Visualization. Zhao Zhang: Visualization. Chunling Zhao: Supervision, Conceptualization. Weichao Sun: Writing – review & editing, Supervision, Funding acquisition, Conceptualization. Qian Yi: Writing – review & editing, Writing – original draft, Supervision, Funding acquisition, Conceptualization.

Availability of data and materials

Not applicable.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Funding

This research was supported by the Shenzhen Medical Research Fund (No. A2403030); the joint foundation of Luzhou Government and Southwest Medical University (No. 2024LZXNYDJ104); Scientific Research Foundation of Southwest Medical University (No.2021ZKMS009, NO.2021ZKQN012), Shenzhen Science and Technology Projects (No. JSGG20220831110400001, KCXFZ20230731093059012); the National Under-graduate Training Programs for Innovation and Entrepreneurship (No.S202310632325, No.2024361).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Abbreviations

MP

Microplastics

NP

Nanoplastics

APCs

Antigen-presenting cells

PP

Polypropylene

PS

Polystyrene

PET

Polyethylene terephthalate

PVC

Polyvinyl chloride

PE

Polyethylene

PUR

Polyurethane

PS-MP

Polystyrene microplastics

PS-NP

Polystyrene nanoparticles

PLA

Polylatic acid

CA

Cellulose acetate

IL-1β

Interleukin-1β

TNF-α:

Tumor necrosis factor-α

TLR4

Toll-like receptor 4

MCP-1

Monocyte chemoattractant protein-1

CXCL2

Macrophage inflammatory protein-2

HMOX-1

Heme oxygenase-1

PTFE-MPs

Polytetrafluoroethylene microplastics

PS-NH2

Polystyrene nanoparticles

ROS

Reactive oxygen species

MAPK

Mitogen-activated protein kinase

NF-κB

Nuclear factor kappa B

NO

Nitric oxide

HIF-1α

Hypoxia-inducible factor 1-alpha

IBD

Inflammatory bowel disease

IRF5

Interferon regulatory factor 5

PMMA

Polymethyl methacrylate

ET

Extracellular trap structures

CTX

Cyclophosphamide

FMT

Fecal microbiota transplantation

Py-GC/MS

Pyrolysis gas chromatography/mass spectrometry

MIF

Macrophage migration inhibitory factor

MDA

Malondialdehyde

ECM

Extracellular matrix

PBMCs

Peripheral blood mononuclear cells

IFNγ

Interferon-γ

LPS

Lipopolysaccharides

TGF-β:

Transforming growth factor beta

GSDMD

Gasdermin D

NLRP3

Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3

O₂•−:

Superoxide anion

H₂O₂:

Hydrogen peroxide

•OH

Hydroxyl radical

GPX

Glutathione peroxidase

CAT

Catalase

SOD

Superoxide dismutase

GSSG/GSH

Oxidized glutathione/Reduced glutathione

GR

Glutathione reductase

NAC

N-acetylcysteine

NOS

Nitric oxide synthase

iNOS

Inducible nitric oxide synthase

Data availability

No data was used for the research described in the article.