Fine particulate matter manipulates immune response to exacerbate microbial pathogenesis in the respiratory tract

Abstract

Particulate matter with a diameter ≤2.5 μm (PM_2.5) poses a substantial global challenge, with a growing recognition of pathogens contributing to diseases associated with exposure to PM_2.5. Recent studies have focused on PM_2.5, which impairs the immune cells in response to microbial infections and potentially contributes to the development of severe diseases in the respiratory tract. Accordingly, changes in the respiratory immune function and microecology mediated by PM_2.5 are important factors that enhance the risk of microbial pathogenesis. These factors have garnered significant interest. In this review, we summarise recent studies on the potential mechanisms involved in PM_2.5-mediated immune system disruption and exacerbation of microbial pathogenesis in the respiratory tract. We also discuss crucial areas for future research to address the gaps in our understanding and develop effective strategies to combat the adverse health effects of PM_2.5.

Shareable abstract

PM_2.5 exposure significantly impacts the respiratory immune response, increasing susceptibility to microbial infections. This review summarises the mechanisms involved in respiratory health and the need for further research on mitigating these effects. https://bit.ly/3L1Cks2

Introduction

Air quality is a crucial issue that warrants concern since the air we breathe can gradually affect our health. According to an estimation made by the World Health Organization (WHO) in 2021 and the Institute for Health Metrics and Evaluation's Global Burden of Disease in 2019, approximately 6–7 million deaths can be attributed to the joint effects of ambient and household air pollution [1]. Crucially, an increase has been noted in both the mortality and disease burden associated with ambient air pollution, whereas these factors decreased for household air pollution [2, 3].

To offer a quantitative, health-based recommendation for air quality, the WHO published air quality guidelines (AQGs) for ambient pollutants in 2005 and updated them in 2021 [4]. These guidelines help regulators formulate policies aimed at reducing the health burden caused by exposure to air pollution. In the AQGs, the levels of particulate matter (PM), ground-level ozone (O₃), nitrogen dioxide, sulphur dioxide and carbon monoxide (were listed as major concerns [5]. Research has mostly focused on PM with a diameter ≤2.5 μm (PM_2.5), owing to its compositional heterogeneity and severity [6, 7]. More than 90% of the world's population is exposed to higher PM levels compared to the recommendations of the AQGs [8]. High concentrations of PM have been recorded in Southeast Asia, the Eastern Mediterranean and Western Pacific regions, leading to an elevated mortality rate [9]. For PMs, especially PM_2.5, approximately 64% of deaths were attributed to ambient air pollution, whereas 36% of deaths were attributed to household air pollution [10]. The welfare losses caused by air pollution were 40% higher than those in the 2013–2016 evaluation and were estimated to be $8.1 trillion, equivalent to 6.1% of the global gross domestic product in 2019 [11]. The highest welfare losses were reported in middle-income countries with ambient air pollution, whereas low-income countries suffered from household air pollution [12]. Consequently, the morbidity and mortality rates of respiratory diseases are major issues affecting individuals with low or medium socioeconomic status who are exposed to poor living conditions [13].

Respiratory diseases comprise three of the top ten causes of death, with COPD being the third, lower respiratory tract infections (LRTIs) being the fourth and pulmonary cancers being the sixth [14]. The Forum of the International Respiratory Society identified five major lung problems, termed the “big five”, and included COPD, asthma, acute LRTIs, tuberculosis and lung cancer [15]. While the exact mechanisms remain unclear, there appears to be an inseparable interaction between exposure to air pollution and respiratory infections in pulmonary infectious diseases, such as bacterial pneumonia or viral infections. This interaction leads to increased severity and mortality [16, 17]. Therefore, we conducted searches for studies on ambient air pollution across three databases, namely PubMed, Web of Science and Cochrane, using the keywords: (“PM_2.5” OR “air pollution”) AND (“immune response” OR “immunosuppression” OR “cytokines” OR “innate immunity” OR “adaptive immunity”) AND (“respiratory infections” OR “virus” OR “bacteria”). We then applied database-specific filters to include animal studies, in vitro cell culture experiments and clinical research. Our inclusion criteria were: 1) relevance to the topic and publication before 2024, 2) articles written in English, 3) peer-reviewed animal experiments, cell culture experiments, clinical trials and observational studies, and 4) studies related to respiratory infections. Conversely, exclusion criteria included: 1) studies focusing on nonimmunological parameters or lacking specific immune response outcomes and 2) studies investigating other pollutants. In this review, we discuss how PM_2.5 orchestrates immune responses and contributes to the promotion of microbial respiratory infections and pathogenesis.

Composition of PM_2.5

PM is a complex mixture of airborne particles and liquid droplets that can be released by primary or secondary resources [18]. Primary resources are linked to anthropogenic factors, such as vehicle usage, industries and residential heating, or natural elements such as windblown dust, pollen, soil erosion, forest fires and dust storms. Secondary resources are formed within the atmosphere via chemical reactions, which generally result in the formation of sulphur dioxide, nitrogen oxides, ammonia and certain organic compounds [19]. The PM categories are characterised by their diameters. PM₁₀, also called coarse particles, are smaller than 10 µm in diameter, PM_2.5, referred to as fine particles, are smaller than 2.5 µm in diameter and PM_0.1, also called ultrafine particles, are less than 0.1 µm in diameter [20]. The compositions and concentrations of PMs are highly correlated with geographical conditions and climate extremes, and inhaled PMs vary significantly over time and space and may have a remarkably different impact on PM-associated diseases [21, 22]. PM₁₀ is directly emitted from natural sources or activities that disturb nature, whereas PM_2.5 is predominantly expelled from anthropogenic sources [23, 24].

By analysing their ion composition, the chemical composition of PMs can be sorted into six categories, as follows: sulphate (assumed to be ammonium sulphate), nitrate (assumed to be ammonium nitrate), organic mass, elemental or black carbon, fine soil, and sea salt (coarse mass) [25]. PMs are usually dominated by organic groups related to urban aerosols, followed by sulphate–nitrate–ammonium ions, which are considered secondary resources in different regions [26, 27]. In contrast, PM₁₀ comprises 10–20% of the ion components originating from fine soil and sea salt, which may originate from sand and dust storms [28]. While PM_2.5 poses the greatest danger to human health, PM₁₀–PM_2.5 can also be a concern as it can invade the upper airway and the larger airways of the lungs, mediating injury via inflammation or other mechanisms [29, 30].

Several toxic components, including polycyclic aromatic hydrocarbons (PAHs), aliphatic/chlorinated hydrocarbons, nitro PAHs/ketones/quinones and other potential toxic elements (PTEs), such as cadmium, lead [31], zinc [32], nickel, chromium, arsenic or copper, are usually incorporated in the PM_2.5. These are enriched and fluctuate in particular regions and different seasons [33–35]. 16 PAHs are listed as high-priority pollutants by the Environmental Protection Agency, including naphthalene, acenaphthylene, acenaphthene, fluorene, phenanthrene, anthracene, fluoranthene, pyrene, benzo[a]anthracene, chrysene, benzo[b]fluoranthene, benzo[k]fluoranthene, benzo[a]pyrene, benzo[g,h,i]perylene, indeno[1,2,3-c,d]pyrene and dibenz[a,h]anthracene, due to their potential toxicity to human and other organisms [36]. PAHs can be further categorised based on their aromatic rings and molecular weight. Low molecular weight (LMW) and intermediate molecular weight (IMW) PAHs are composed of two to three rings and four rings, respectively, and high molecular weight (HMW) PAHs, which contain at least five ring structures, are largely bound to particles. LMW PAHs are typically found in the atmosphere, predominantly in the vapour phase, whereas IMW PAHs are distributed between the vapour and particulate phases [37]. Among these PAHs, benzo[a]pyrene is considered the most toxic with high carcinogenicity [38]. PAHs also mediate the dysfunction of metabolic enzymes and produce reactive oxygen species (ROS) and DNA adducts, triggering inflammation, DNA mutations and tumorigenesis [39, 40].

Meanwhile, the varieties of inflammatory responses or disease outcomes are correlated with PTEs owing to the diverse range of components that are incorporated. For example, cadmium accumulation in immune cells not only alters their ability to secrete cytokines and induces ROS production to trigger cell death, but also influences the frequency and distribution of immune cell subsets that are recruited into the affected tissues or organs [41]. Nickel, chromium and arsenic significantly increase the prevalence of paediatric, acute upper and lower respiratory diseases, and pneumonia during flu seasons [42]. Nevertheless, co-exposure of lead with arsenic, cadmium or mercury induces the onset of asthma [41]. Although more evidence is required, the level of metal ions in PM_2.5 may be crucial for evaluating the risk of inflammatory diseases and tumours.

PM_2.5 manipulates immune response and promotes disease development

Given its small particle size, 1) the inhaled PM_2.5 is not only trapped in the upper respiratory tract and injures the integrity of the epithelial cells and disrupts their functions but is also capable of penetrating into the lower respiratory tract to destroy the alveolar epithelial cells. 2) Although macrophages in the lung play a critical role in eliminating inhaled particles and maintaining immune homeostasis by regulating cytokine secretion, the toxic components embedded in PM_2.5 disrupt their phagocytosis and autophagy abilities and even alter their differentiation process. 3) PM_2.5 even disrupts the T-helper (Th) 1/Th2 balance of T-cell differentiation, leading to inappropriate cytokine expression, enhanced immune cell infiltration and inflammatory responses in the respiratory tract (figure 1). In addition to severe lung injuries, these dysregulated cytokine secretions induced by PM_2.5 are correlated with tumorigenesis. Therefore, in this section, the impact of PM_2.5 on immune responses and their associated diseases is discussed.

FIGURE 1.

Particulate matter with a diameter ≤2.5 μm (PM_2.5) impairs immune function and promotes disease development. Schematic illustration of the mechanism underlying the suppression of the immune system mediated by PM_2.5. a) Representation of the respiratory system in a healthy individual and b) The airway status during PM_2.5 exposure. Upon exposure, PM_2.5 leads to mitochondrial dysfunction and induces reactive oxygen species (ROS) production in epithelial cells. Excessive ROS disrupts the integrity of the epithelial barrier and cilia, which impairs mucociliary clearance and allows bacteria to adhere to and colonise the upper respiratory tract. PM_2.5 even penetrates deeply into the lower respiratory tract to irradiate the alveolar epithelial cells and trigger ROS production. Injured alveolar epithelial cells and macrophages thereby produce proinflammatory cytokines and chemokines to recruit immune cells into the alveoli. However, the infiltration of immune cells into the alveoli exacerbates the lung damage. Meanwhile, monocyte-derived macrophages and T-cells further undergo polarisation in response to various costimulants, potentially resulting in alveolar fibrosis, lung adenocarcinoma or gas exchange failure. EGFR: epidermal growth factor receptor; IFN-β: interferon-β; IL: interleukin; IM: interstitial macrophage; MΦ: macrophage; PM₁₀: PM with a diameter ≤10 μm; Th: T-helper cell; TNF-α: tumour necrosis factor-α.

PM_2.5 disrupts the integrity of the epithelial barrier and the cytokine expression, the first line of defence against pathogens

Due to the diameter of PMs, PM₁₀–PM_2.5 are typically trapped in the upper airways (nasal cavity, pharynx and larynx) to stimulate respiratory symptoms. In contrast, smaller particles (diameter ≤2.5 μm) are capable of penetrating more deeply into the lower respiratory tract (bronchioles and alveoli) or other organs by passing through the blood–air exchange system, thereby leading to severe disruptions [43]. Airway epithelial cells serve as the first line of defence against microbes and noxious stimuli by providing mucociliary clearance, secreting antimicrobial proteins and peptides, and interacting with specific immune cells to maintain homeostasis or facilitate immune reactions [44]. Exposure to PM_2.5 causes ciliary disruption and increases mucus production [45, 46], which impairs mucociliary clearance and allows bacteria to adhere to and colonise the airway [47]. With ROS production induced by PM_2.5, epithelial cells even reduce the expression of β-defensin-2, which is known as a skin antimicrobial peptide for the prevention of Gram-negative bacterial infections [48]. Meanwhile, epithelial cells, when stimulated by PM_2.5, undergo mitochondrial fragmentation and dysfunction. This process leads to apoptosis through the abundant production of ROS or senescence and ferroptosis due to the downregulation of sirtuin 3, which is an essential factor in regulating mitochondrial metabolism and homeostasis [49]. Therefore, the changes in the integrity of the epithelial barrier and the function of epithelial cells generate a favourable environment for pathogen invasion [50]. Moreover, the production of excessive ROS mediated by PM_2.5 enhances epithelial–mesenchymal transition, leading to carcinogenesis and fibrosis [51]. In addition to directly disrupting the integrity of epithelial barrier and their functions as the first line of defence against pathogens, PM_2.5 stimulates the expression and secretions of proinflammatory cytokines including interleukin (IL)-6, IL-8, IL-1β and tumour necrosis factor-α (TNF-α) to accelerate lung injury and reduce the secretion of antiviral cytokine interferon-β (IFN-β) for protecting viral infection [52, 53]. Therefore, PM_2.5 increases the prevalence, incidence and mortality of respiratory diseases.

PM_2.5 alters the distribution of the alveolar macrophage population and its functions in the lung

Alveolar macrophages (AMs), including tissue-resident (TR) AMs (monocyte-derived AMs (Mo-AMs) and interstitial macrophages (IMs), are the major macrophages distributed in the lung [54]. IMs maintain lung homeostasis and prevent immune-mediated allergic airway inflammation [55]. In comparison to TR-AMs, Mo-AMs are more efficiently triggered by stimuli and respond to them more effectively [56]. Gangwar et al. [32] found that chronic exposure to PM_2.5 increased the recruitment of monocytes from the bone marrow to the lung, followed by development and incorporation into the AM population. AMs in the lungs serve as the first line of defence for consuming inhaled particles and maintaining immune homeostasis in the lung [32]. However, exposure to PM_2.5 enhances apoptosis and prevents the proliferation of TR-AMs, leading to a dramatic reduction in AM populations [32].

Macrophages differentiate into either classic (M1) or alternative (M2) macrophages after being activated by environmental stimulants [57]. Both M1 and M2 macrophages have distinct functions in modulating immune responses in the lung tissues [58]. M1 macrophages are capable of producing proinflammatory cytokines, such as IL-6, IL-12 and TNF-α, whereas M2 macrophages elicit contrasting anti-inflammatory responses (arginase-1, IL-10, CC chemokine ligand (CCL)17 or CCL22) for repairing damaged tissues, angiogenesis and regulating metabolism [58]. PM_2.5 preferentially promotes the differentiation of Mo-AMs into M1 macrophages; however, it disrupts their ability to induce phagocytosis and autophagy [59, 60]. Interestingly, PM_2.5 also increases M2 macrophage polarisation via TNF-α-induced protein 8-like 2 and an activated phosphoinositide 3-kinase/protein kinase B pathway, whereas heavy metals incorporated in PM_2.5 trigger M2 macrophages to produce cytokines, mediating allergic responses [60, 61].

In addition to eliminating inhaled particles and secreting certain cytokines to maintain immune homeostasis, AMs in the lungs play a critical role in regulating the cytokines produced by T-cells, particularly in mediating the Th1/Th2 balance to eradicate pathogens [62]. However, PM_2.5 exposure appears to disturb the Th1/Th2 balance. Both Ma et al. [63] and Piao et al. [64] found that PM_2.5 exposure preferentially increases Th2/Th17 cytokines, but not Th1 cytokines, leading to enhanced cell infiltration and inflammatory responses in the respiratory tract.

To date, only a few studies have explored the influence of PM_2.5 on IMs. Surprisingly, PM_2.5 significantly increases IM population in the lung and elevates IL-1β secretion, which stimulates alveolar type II epithelial cells to express epidermal growth factor receptor for inducing tumorigenesis, leading to lung adenocarcinoma [65]. This indicates the potential effects of PM_2.5 on promoting cancer progress.

PM_2.5 stimulates inflammation cascades for recruiting immune cells to injured sites

Many pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), C-type lectin receptors, retinoic acid-inducible gene-I-like receptors, nucleotide-binding domains and leucine-rich repeat-containing proteins (NLRs), are expressed in macrophages, dendritic cells, neutrophils and epithelial cells [66]. PRRs serve as immune sensors to recognise invading pathogens or environmental stimulants and initiate innate immunity. In particular, inflammasomes assemble to trigger caspase activities [67]. Among these PRRs, NLR family members are typically a part of the inflammasome [68]. Consumption of PM_2.5 by macrophages or epithelial cells triggers the signalling cascade, leading to the formation of nucleotide-binding oligomerisation domain-like receptor family, pyrin domain containing protein 3 (NLRP3) inflammasome and selection of proinflammatory cytokines TNF-α and IL-1β, resulting in lung fibrosis [69]. Moreover, these pro-inflammatory cytokines recruit eosinophils and neutrophils, causing substantial lung damage [70]. Therefore, the depletion of NLRP3 in macrophages alleviates this phenomenon [71]. However, Tao et al. [72] showed that activation of the NLRP3 inflammasome was prevented during influenza A virus (IAV) infection after PM_2.5 exposure. Further studies on the influence of PM_2.5 on inflammasomes may be warranted to comprehensively analyse the impact of PM_2.5 on respiratory immune functions and its correlation with microbial infectivity.

PM_2.5 exacerbates bacterial infectivity in the respiratory system

Bacteria, identified as the predominant microorganisms associated with PM_2.5, contribute significantly to the dissemination of respiratory diseases [73]. Epidemiological evidence suggests a positive correlation between PM_2.5 exposure and elevated susceptibility to respiratory pathogen infections [73, 74]. PM_2.5 negatively impacts macrophage functions, such as phagocytosis and nitric oxide production, ultimately exacerbating Streptococcus pneumoniae invasion [59]. This effect was also observed in vivo by Shears et al. [75], who found increased pneumococcal loads in the lungs and the development of invasive pneumococcal disease following exposure to diesel exhaust particles. Exposure to air pollution elevates the susceptibility to Staphylococcus aureus infection in the respiratory tracts of rats [76]. This heightened vulnerability is attributed to the reduction in natural killer cells, which subsequently suppress phagocytosis activity [76]. Furthermore, PM_2.5, synergised with Pseudomonas aeruginosa to impede alveolar macrophage function, causes more severe respiratory system injuries via a process closely related to the activation of the mammalian target of rapamycin signalling pathway [77].

Some researchers believe that PM_2.5 can enhance inflammation in immune cells. Consequently, increased inflammation after bacterial invasion can lead to severe infections (table 1). PM_2.5 has been implicated in the disturbance of the secretion of proinflammatory cytokines and iron metabolites, accelerating the growth of Mycobacterium tuberculosis and its transformation into an invasive mycobacterium [78]. Moreovcer, significant pathological damage was observed in the lung tissues of mice co-stimulated by PM_2.5 and Pseudomonas aeruginosa, resulting from the increased expression levels of IL-6, IL-8 and TNF-α via the NF-κB pathway [79].

TABLE 1.

Experimental models for investigating the influence of particulate matter with a diameter ≤2.5 μm (PM_2.5) on bacterial infections

Experimental platform	Pathogen	Immune response	Reference
PM2.5 suppresses immune response and exacerbates bacterial infection
Sprague–Dawley rats	Listeria monocytogenes	Exposure to diesel exhaust particles decreased the production of macrophage-derived antimicrobial oxidants in response to Listeria	[113]
BALB/c mice	Streptococcus pneumoniae	Soluble components of concentrated ambient particles inhibit the internalisation of Streptococcus pneumoniae by macrophages	[114]
A549 cells	Streptococcus pneumoniae	PM2.5 stimulates Streptococcus pneumoniae to adhere to respiratory epithelial cells	[115]
Sprague–Dawley rats	Klebsiella pneumoniae	PM2.5 impairs the bronchial ciliary system and the interaction of cytokines, increasing susceptibility to bacterial infection	[80]
Wistar rats	Staphylococcus aureus	PM2.5 downregulates macrophage phagocytosis and reduces pulmonary natural killer cells	[76]
Clinical study (a systemic review)	Mycobacterium tuberculosis	PM2.5 suppresses immune defence, increasing an individual's susceptibility to development of active TB and TB-related mortality	[78]
CD1, C57BL/6 and BALB/c mice	Streptococcus pneumoniae	PM loading of macrophages is associated with reduced phagocytic killing activity and promotes inflammation in the context of bacterial challenge	[75]
RAW 264.7 cells and BALB/c mice	Streptococcus pneumoniae	PM2.5 impedes the macrophage function to exacerbate bacterial infection	[59]
C57BL/6 mice	Pseudomonas aeruginosa	PM2.5 and Pseudomonas aeruginosa synergistically dampen alveolar macrophage function and induce inflammation through the mTOR pathway	[77]
PM2.5 enhances immune response and promotes inflammation
Clinical study (a systemic review)	Mycoplasma pneumoniae	The induction of oxidative stress mechanisms and the modulation of the host immune system are attributed to the interaction between PM2.5-associated metal complexes and Mycoplasma pneumoniae This interaction is assumed to occur through the TLRs and/or NF-κB pathway	[116]
RAW 264.7 cells and BALB/c mice	Pseudomonas aeruginosa	Co-stimulation with PM2.5 and Pseudomonas aeruginosa increases the expression of IL-8, IL-6 and TNF-α, leading to severe inflammation	[79]

IL: interleukin; mTOR: mammalian target of rapamycin; TB: tuberculosis; TLR: Toll-like receptor; TNF-α: tumour necrosis factor-α.

As indicated earlier, PM_2.5 compromises bacterial clearance by disrupting immune responses or inducing severe inflammation, ultimately leading to tissue damage [75, 80, 81]. Notably, exposure to PM_2.5 has a pronounced impact on vulnerable populations, including children, the elderly and individuals with underlying or potential pulmonary diseases [82]. Exposure to PM_2.5 elevates the potential risk of initial acquisition of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa in young children with cystic fibrosis [83]. PM_2.5 poses a significant challenge in developed countries, with an increasing number of pathogens identified as those that cause diseases following exposure. However, a gap remains in robust research on molecular mechanisms and effective treatment strategies.

PM_2.5 alters microbiota composition in the respiratory tract

The microbiome has been identified as a critical player in defending the respiratory tract against pathogen colonisation and in influencing the development of respiratory structures and immunity. Microbial dysbiosis disrupts the host homeostasis and promotes disease progression. Notably, alterations in the microbiota can directly stimulate pulmonary inflammation and oxidative stress in response to PM_2.5 [84]. Furthermore, exposure to PM_2.5 is related to a decrease in lung microbiota diversity, enhanced susceptibility to pneumococcal infection and exacerbated lung pathogenesis [85]. Additionally, exposure to PM_2.5 correlates with changes in the respiratory microbiome, affecting both normal flora and potential pathogens, potentially compromising pulmonary function in affected individuals [31]. Remarkably, antibiotic treatment alleviates pulmonary inflammation and oxidative damage in mice by promoting microbiota diversity, decreasing the abundance of Proteobacteria and increasing the abundance of Bacteroidota [84]. As the microbiome is established during childhood, the determinants of lung bacterial colonisation in children are associated with the mode of delivery and feeding type [86]. This evidence suggests that air pollution is associated with respiratory diseases in children [87]. Furthermore, various sources of PMs affect microbial profiles in different ways. These results contribute to a better understanding of the impact of air pollution on organismal microbiota and underscore the importance of safeguarding the health of the respiratory system.

PM_2.5 impedes immune response against viral infections

Exposure to particulate pollution is known to affect the respiratory system and damage pulmonary function (table 2) [70, 88–90]. Exposure to air pollution also critically influences the ability of viruses to infect cells to cause severe infection [91, 92]. For instance, PM_2.5 promotes the entry of severe acute respiratory syndrome coronavirus 2 into host cells by enhancing the expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) in human alveolar cells [93]. This increase in viral entry contributes to the severity of coronavirus disease 2019, placing an additional burden on medical care systems during the pandemic [94]. PM_2.5 promotes IAV infection by enhancing the expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) [95, 96]. Additionally, ACE2 and TMPRSS2 are critical for wound healing and inflammation [97]; whereas ICAM-1 and VCAM-1 are required for the recruitment of leukocytes to inflammatory lesions [98]. The promotion of the expression of these molecules by PM_2.5 may enhance inflammatory responses that are required for viral clearance.

TABLE 2.

Immune responses induced by particulate matter with a diameter ≤2.5 μm (PM_2.5)

Experimental platform	PM2.5 exposure time #	Immune response	Reference
Immune responses enhanced by PM2.5
Peritoneal macrophages isolated from C57BL/6 mice	Short-term	PM2.5 induces polarisation of macrophage through induction of ROS	[105]
Human umbilical vein cell line, EA.hy926	Short-term	PM2.5 induces ERK/AKT/NF-κB signalling pathway and results in increased ICAM-1 and VCAM-1 expression	[96]
Human bronchial epithelial cells, 16HBE cells	Short-term	PM2.5 induces the NLRP3/caspase-1 pathway and results in cell-secreted inflammatory cytokines	[70]
Murine model	Short-term	PM2.5 increases ACE2 and TMPRSS2 expression	[93]
BALB/c mice	Long-term (6 days)	PM2.5 increases ACE2, COX-2 and HO-1 expression in several organs, including lung, heart, liver and brain	[103]
BALB/c mice	Long-term (14 days)	PM2.5 induces the NLRP3/caspase-1 pathway and results in mice lung inflammatory	[70]
BALB/c mice	Long-term (90 days)	PM2.5 activates the Notch signalling pathway and results in increased Th1/Th2 and Th17/Treg cells	[108]
C57BL/6 mice	Long-term (12 weeks)	PM2.5 regulates TNF-α and IL-6, leading to lung damage	[117]
Human experiment: traffic policemen	Long-term (4 months)	PM2.5 elevates hsCRP, IgM, IgG and IgE	[106]
Immune responses reduced by PM2.5
Human experiment: traffic policemen	Long-term (4 months)	PM2.5 decreases the expression of IgA and CD8+ T-cells	[106]

^#: Short-term exposure: exposure to PM_2.5 within 24 h; long-term exposure: exposure to PM_2.5 for more than 24 h. ACE2: angiotensin converting enzyme 2; AKT: protein kinase B; COX-2: cyclooxygenase 2; ERK: extracellular signal-regulated kinase; HO-1: haem oxygenase 1; hsCRP: highly sensitive C-reactive protein; ICAM-1: intercellular adhesion molecule-1; IL: interleukin; NLRP3: nucleotide-binding oligomerisation domain-like receptor family, pyrin domain containing protein 3; ROS: reactive oxygen species; Th: T-helper cell; TMPRSS2: transmembrane protease serine 2; TNF-α: tumour necrosis factor-α; Treg: regulatory T-cell; VCAM1: vascular cell adhesion molecule-1.

Exposure to PM_2.5 and simultaneous infection by IAV or coxsackievirus B3 significantly enhances the expression of proinflammatory cytokines, such as IL-6, TNF-α and transforming growth factor (TGF)-β, in both cell and mouse models [99, 100]. The induction of the expression of these proinflammatory cytokines leads to hyperinflammation and, in some cases, triggers a cytokine storm, resulting in severe symptoms and increased mortality [101, 102]. Botto et al. [103] showed that PM_2.5 activates cyclooxygenase 2 to enhance the expression of proinflammatory lipids, which mediate widespread inflammation and tissue damage, exacerbating cytokine storms. Additionally, exposure to PM_2.5 leads to the overproduction of ROS in macrophages [95, 104]. When the production of ROS is inhibited, the expression of granulocyte−macrophage colony-stimulating factor, IL-6 and TNF-α is reduced, suggesting that the release of inflammatory cytokines induced by PM_2.5 depends on ROS [105]. Furthermore, PM_2.5 exposure has been linked to the proinflammatory M1 macrophage polarisation, which further promotes the release of cytokines, such as IL-6, TNF-α, TGF-β and IL-18 [105].

Apart from affecting the innate immune response, PM_2.5 exposure influences adaptive immunity. PM_2.5 exposure elevates highly sensitive C-reactive protein, IgM, IgG, IgE and CD4⁺Foxp3⁺ cells (regulatory T-cells (Tregs)) and decreases the expression of IgA and production of CD8⁺ T-cells [99, 106]. These changes in adaptive immunity increase inflammatory cytokine production, promoting cytokine storms and allergic reactions [107]. PM_2.5 exposure elevates Th1/Th2 and Th17/Treg cell ratios in both healthy mice and mice with COPD via the Notch signalling pathway [108]. This T-cell imbalance is associated with an increased production of pro-inflammatory cytokines, leading to inflammatory disorders and exacerbation of the immune response [109]. Moreover, prolonged exposure to PM_2.5 increases the infiltration of inflammatory cells, leading to chronic inflammatory responses and pulmonary fibrosis [70, 88, 89], which increases the risk of acute respiratory distress syndrome [36] and mortality [110]. These studies suggest that PM_2.5 accelerates the progression of severe cytokine storms during respiratory viral infections (table 3).

TABLE 3.

Immune responses and potential effects induced by particulate matter with a diameter ≤2.5 μm (PM_2.5) on viral infections

Experimental platform	PM2.5 exposure time #	Pathogen	Immune response	Reference
Immune responses/effects enhanced by PM2.5 on virus infection
BALB/c mice	Short-term	Coxsackievirus B3	PM2.5 enhances Treg cell and IL-6, TNF-α and TGF-β	[99]
Murine model	Short-term	Influenza A virus	PM2.5 increases secreted IL-6, IL-1β and IFN-β in the lungs	[100]
C57BL/6	long-term	SARS-CoV-2	PM2.5 increases TNF-α, TGF-β1 and IL-6 in the lungs	[118]
BABL/c mice	Long-term (>1 week)	Influenza A virus	PM2.5 drives influenza A virus deep into the lower respiratory tract and distant organs	[119]
Immune responses reduced by PM2.5 on virus infection
Macrophage isolated from  C57BL/6 mice	Short-term	Influenza A virus	PM2.5 decreases IL-1β and IFN-β production	[72]
A549 cells	Short-term	Vesicular stomatitis virus	PM2.5 degrades p-IRF3 via ubiquitination, resulting in decreased IFN-β levels and promoting viral replication	[111]
C57BL/6 mice	Long-term (3 days)	Influenza A virus	PM2.5 decreases IL-1β and IFN-β production	[72]
Murine model	Long-term (2 weeks)	Influenza A virus	PM2.5 suppresses influenza A-induced secreted IL-6, IL-1β and IFN-β in the lungs	[100]

^#: Short-term exposure: exposure to PM_2.5 within 24 h; long-term exposure: exposure to PM_2.5 for more than 24 h. IFN-β: interferon-β; IL: interleukin; p-IRF3: phosphorylated interferon regulatory factor 3; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TGF: transforming growth factor; TNF-α: tumour necrosis factor-α; Treg: regulatory T-cell.

Exposure to PM_2.5 is also linked to the suppression of the interferon type-1 pathway, potentially rendering the immune system less effective against viral infection [72, 100, 111]. Various studies have identified distinct pathways through which PM_2.5 exerts this effect. For instance, PM_2.5 exposure increases 2,3,7,8-tetrachlorodibenzo-p-dioxin inducible poly(ADP-ribose) polymerase expression by activating the aryl hydrocarbon receptor, resulting in the suppression of the NLRP3 inflammasome (responsible for the expression of IL-1β and IL-18) and IFN-β expression [72]. These effects can potentially weaken the immune system, rendering the host more susceptible to viral infections [112]. Additionally, PM_2.5 degrades phosphorylated interferon regulatory factor 3 via ubiquitination, resulting in decreased IFN-β levels and promoting the replication of the vesicular stomatitis virus (VSV) [111]. Meanwhile, Ma et al. [100] showed that prolonged exposure to PM_2.5 for more than 7 days leads to the inhibition of the secretion of inflammatory cytokines, IFN-β and IL-6 in pulmonary macrophages via downregulation of lysine demethylase 6A (Kdm6a) expression, which is required to regulate the transcription of IL-6 and IFN-β. Tao et al. [72] also observed that exposure to PM_2.5 for 3 and 6 days suppresses the expression of IL1-β, either in a single-exposure scenario or in the presence of H1N1/PR8 infection. These studies suggest that prolonged PM_2.5 exposure suppresses, instead of inducing, the expression of inflammatory cytokines. However, the specific mechanisms and timelines underlying this phenomenon require further investigation.

The inconsistency of the effects of PM_2.5, including the duration and experimental models used for PM_2.5, on viral infection and inflammation may be multifactorial. Differences in the pathogenic mechanisms induced by viral infections and other factors, such as chronic diseases caused by inflammation and vaccination, may also contribute to varying outcomes. Age, sex and genetic variations may influence inflammatory responses. However, the precise mechanisms underlying this phenomenon remain unclear and require further investigation. Ma et al. [100] provided a more robust mouse model to monitor immune responses and inflammatory injuries after short-term (within 24 h) and long-term exposure to PM_2.5, followed by IAV infection. Their results concluded that PM_2.5 exposure for more than 1 week significantly reduced the secretion of inflammatory factors and downstream immune-stimulated gene responses, leading to decreased immunity for clearance of IAV and lung injuries.

Conclusions and perspectives

The relationships between PM_2.5 and health problems are well-documented. PM_2.5 can be inhaled deeply into the lungs and potentially transport a variety of pollutants, including pathogens. Current studies rely predominantly on cell-based assays or animal models, with limited emphasis on in-depth clinical research in humans. Although these experimental approaches provide valuable insights, their application to human health remains limited. Additionally, there are a limited number of studies investigating the potential mechanism through which PM_2.5 affects the microbiota composition in the human respiratory tract. Furthermore, extensive exploration of the long-term immune responses associated with microbiota dysbiosis due to PM_2.5 exposure is needed. The important microbial metabolites involved in PM_2.5, which exacerbate pathogen-induced pulmonary pathogenesis, must be studied. Understanding the potential limitations of the current studies and promoting more comprehensive clinical investigations are crucial for filling the gap between experimental findings and practical applications in humans.

Points for clinical practice

• Clinicians should be aware of the exacerbating effects of PM_2.5 on respiratory infections, particularly in vulnerable populations such as children, the elderly and individuals with underlying respiratory conditions.

• It is important to continuously monitor air quality and advise patients on minimising exposure to PM_2.5, particularly during high pollution periods.

• Integrating information about air pollution and its health impacts into patient education can aid in managing and preventing respiratory condition exacerbations.

Questions for future research

• What are the long-term effects of chronic PM_2.5 exposure on the human respiratory immune system?

• What are the underlying molecular mechanisms that link PM_2.5 exposure to increased susceptibility to respiratory infections?

• Can interventions targeting the immune response significantly mitigate the adverse health effects of PM_2.5 exposure, thereby improving public health outcomes?