Environmental Pollutants and Phosphoinositide Signaling in Autoimmunity

Abstract

Environmental pollution stands as one of the most critical challenges affecting human health, with an estimated mortality rate linked to pollution-induced non-communicable diseases projected to range from 20% to 25%. These pollutants not only disrupt immune responses but can also trigger immunotoxicity. Phosphoinositide signaling, a pivotal regulator of immune responses, plays a central role in the development of autoimmune diseases and exhibits high sensitivity to environmental stressors. Among these stressors, environmental pollutants have become increasingly prevalent in our society, contributing to the initiation and exacerbation of autoimmune conditions. In this review, we summarize the intricate interplay between phosphoinositide signaling and autoimmune diseases within the context of environmental pollutants and contaminants. We provide an up-to-date overview of stress-induced phosphoinositide signaling, discuss 14 selected examples categorized into three groups of environmental pollutants and their connections to immune diseases, and shed light on the associated phosphoinositide signaling pathways. Through these discussions, this review advances our understanding of how phosphoinositide signaling influences the coordinated immune response to environmental stressors at a biological level. Furthermore, it offers valuable insights into potential research directions and therapeutic targets aimed at mitigating the impact of environmental pollutants on the pathogenesis of autoimmune diseases.

Graphical Abstract

1. INTRODUCTION

Environmental pollution stands as one of the most critical challenges affecting human health (Collaborators, 2016; Landrigan et al., 2018). It involves the introduction of harmful substances or contaminants into the natural environment, with potentially devastating effects on living organisms, ecosystems, and overall environmental quality. Alarmingly, the estimated mortality rate linked to pollution-induced non-communicable diseases is projected to range from 20% to 25%, making it a formidable threat to public health in the modern world (Collaborators, 2016).

Pollutants have the capacity to disrupt immune responses and trigger immunotoxicity, with autoimmunity being a significant category of immune disorders impacting humans (Suzuki et al., 2020). Autoimmunity is characterized by the immune system’s misguided attack on the body’s own cells and tissues. While the exact origins of these disorders remain elusive, a complex interplay of genetic, hormonal, immunological, and environmental factors, including environmental pollutants (Suzuki et al., 2020), plays a substantial role in their development.

Phosphoinositide (PI) signaling, a vital pathway governing immune cell activation and function, has emerged as a key contributor to autoimmune disease pathogenesis (Stark et al., 2015). Recent research has unveiled the impact of cellular stressors, including environmental pollutants, on PI signaling (Chen et al., 2020; Cong et al., 2020). These pollutants, found ubiquitously in our daily surroundings and increasingly prevalent in society, have the potential to disrupt PI signaling and impair immune responses, thereby exacerbating patient symptoms and disease outcomes.

This paper delves into the intricate interplay between environmental pollutants, PI signaling, and autoimmune diseases. We provide an updated overview of stress-induced PI signaling, highlighting prominent pollutants associated with immune diseases and shedding light on the underlying signaling pathways involved. By advancing our comprehension of how PI signaling shapes immune responses to environmental stressors, this review unveils opportunities for innovative research and potential therapeutic targets aimed at mitigating the impact of these increasingly relevant pollutants on the development of autoimmune diseases.

1.1. Autoimmune Diseases

Autoimmune diseases encompass a broad range of conditions, with approximately 80 known disorders affecting millions of individuals worldwide (Rad et al., 2019). These diseases occur when the immune system, including most tissues and organs, which is designed to protect the body from harmful xenobiotics, mistakenly targets healthy cells and tissues (Fig. 1). Such malfunctioning immune responses lead to a diverse array of symptoms and complications. It is estimated that around 3-5 percent of the global population experiences symptoms associated with immune response disorders (Eaton et al., 2007). Common autoimmune diseases include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), chronic tonsillitis, multiple sclerosis (MS), type 1 diabetes (T1D), inflammatory bowel disease (IBD), psoriasis, and Hashimoto’s thyroiditis (HT), among others (Wang et al., 2015). Despite variations in their specific manifestations and target organs, these conditions share a common underlying feature of self-directed immune system dysregulation. Understanding the mechanisms that initiate and facilitate autoimmune diseases and subsequently developing effective therapeutic interventions are critical areas of research in order to alleviate the burden of these chronic conditions on individuals and society.

Fig. 1.

Immune system and autoimmune diseases. The schematic diagram provides an overview of the key components of the immune system and their associated autoimmune diseases. It is important to recognize that autoimmune diseases can manifest in diverse ways and affect multiple organ systems. Furthermore, a single autoimmune disease can arise from various immune system disorders, and the malfunction of specific immune system components can contribute to the development of multiple autoimmune diseases. While certain autoimmune disorders are not exclusively linked to the immune system components listed, the fundamental elements here play a crucial role in their development. The diagram is generated using BioRender.

1.2. Phosphoinositide Signaling

PIs are a family of signaling lipids that play crucial roles in various cellular processes, including intracellular signaling, cytoskeletal dynamics, membrane trafficking, and cell growth and survival (Chen et al., 2020). They are synthesized by the differential phosphorylation of the inositol ring of phosphatidylinositol (PtdIns) lipids at the 3, 4, and 5 positions, leading to the generation of seven distinct phosphorylated forms of PtdIns, including PtdIns3P, PtdIns4P, PtdIns5P, PtdIns(3,4)P₂, PtdIns(3,5)P₂, PtdIns(4,5)P₂, and PtdIns(3,4,5)P₃ (Fig. 2A, B) (Chen et al., 2020). The phosphorylated forms of PtdIns are known as polyphosphoinositides (PIP_ns). PIP_ns are transported, converted, and interchanged through various PI-metabolizing enzymes, such as PI-transfer proteins, kinases, phosphatases, and phospholipases. Once generated, these lipids exert their function through recruiting and regulating the activity of effector proteins through their interaction with specialized lipid binding domains such as PH (pleckstrin homology) (Li, D. et al., 2022; Wang, X. et al., 2014), FYVE (Fab1, YOTB, Vac1, and EEA1) (Eitzen et al., 2019), and PX (Phox homology) (Sato et al., 2001) domains. These phospholipids are canonically considered to be triggered by agonist stimulation and enriched in plasma membranes. However, accumulating evidence continues to expand our conventional understanding of these signaling lipids from the cell surface to endomembrane and from membrane systems into non-membranous compartments like the nucleoplasm where PIP_ns complex with proteins ( Carrillo et al., 2023; Chen, M. et al., 2022; Chen et al., 2020; Tribble et al., 2016). Regardless of subcellular localization, PIP_ns are widely recognized as essential second messengers that hold central positions in various cellular functions. Among these, the key second messenger PtdIns(3,4,5)P₃, generated by phosphoinositide 3-kinase (PI3K), activates the PDK1/mTORC2/Akt/FOXO (pyruvate dehydrogenase kinase isozyme 1/mechanistic target of rapamycin complex 2/Akt/forkhead box O) signaling cascade, which plays important role in proliferation, growth, and survival (Hoxhaj and Manning, 2020) (Fig. 2C). Dysregulation of PI signaling, particularly the PI3K-Akt pathway, has been implicated in many human afflictions, including cancer, neurodegeneration, autoimmunity, and chronic inflammatory diseases, making PI signaling an important area of research for combating these diseases (Bankaitis and Carman, 2019; Kandoth et al., 2013).

Fig. 2.

Phosphoinositides metabolism. (A) Phosphatidylinositol (PtdIns) structure; (B) phosphoinositide metabolism cycle; and (C) PI3K-Akt signaling pathway. The three hydroxyl groups of the inositol ring can be phosphorylated, forming seven distinct phosphoinositide isomers. These phosphoinositide species differ in the number and position of phosphate groups and can be interconverted by phosphoinositide kinases, phosphoinositide phosphatases, and phospholipases.

1.3. Environmental Pollutants

Environmental pollutants can arise from industrial emissions, air, and water contamination, agricultural practices, and other human activities. They exert detrimental effects on human health and have been increasingly recognized as contributors to the development and progression of autoimmune diseases (Alb et al., 2003). Environmental pollutants can be broadly categorized into three main classifications: physical, chemical, and biological (Fig. 3). Physical pollutants include sun exposure, noise, radiation, microplastics, and temperature extremes, which can exert stress on the human body and disrupt typical biological processes. Chemical pollutants encompass many of the commonly recognized and more often discussed compounds such as heavy metals, pesticides, industrial chemicals such as trihalomethanes, and air pollutants which can contaminate air, water, and soil. Lastly, biological pollutants are largely comprised of microorganisms, such as virus, bacteria, and fungi, as well as allergens and toxins produced by living organisms. Given the growing impact of pollution across the globe, the intricate reciprocity between environmental pollutants and PI signaling is an increasingly pertinent research direction due to its significant roles in the development and progression of autoimmune diseases.

Fig. 3.

Environmental Pollutants. This schematic diagram provides an overview of environmental pollutants, broadly categorized into three main groups: physical, chemical, and biological. The symbols represent typical examples discussed in the text with dedicated sections. It’s important to note that each category encompasses additional pollutants not depicted here, and the list of pollutants related to PI signaling and autoimmunity is continuously expanding. This diagram is generated using BioRender.

Recent emphasis has been shown on the connection between environmental stresses and autoimmune diseases (Alb et al., 2003) (Table 1) with substantial intrinsic involvement of PI signaling pathways (Table 2). Understanding these pathways in autoimmune conditions enhances our knowledge of the underlying pathological processes and reveals avenues for effective interventions. This review delves into a comprehensive discussion of various environmental stresses, categorized based on their physical, chemical, or biological designations. We will explore the autoimmune diseases associated with each stressor and examine the precise involvement of PI signaling in the pathological processes of these diseases. By shedding light on the interconnection between environmental stresses, PI signaling, and autoimmune diseases, we aim to provide valuable insights that can expose targets for developing novel therapeutic strategies intended to alleviate the burden of autoimmune conditions on affected individuals.

Table 1.

Environmental Pollutants’ Relative Autoimmune Diseases and Impact on PI Signaling.

Pollution Type	Environmental Pollutants	Relative Autoimmune Diseases	Impact on PI signaling
Physical Pollution	UV	SLE (Cooper et al., 2010; Fava and Petri, 2019; Garcia-Romo et al., 2011; Lood et al., 2016; Wolf et al., 2018), RA (Alex et al., 2020; Arkema et al., 2013), Vitiligo (Baldini et al., 2017; Le Poole, 2021; Wan et al., 2017)	UV exposure induces the assemble of PtsIns4P, PtdIns(4,5)P2, PtdIns(3,4,5)P3, IPMK, PIPn effector p53, and nuclear Akt activation at the DNA damage sites (Chen, M. et al., 2022; Choi et al., 2019; Wang, Y.H. et al., 2017; Wang, Y.H. et al., 2022).
	PM10/PM2.5	RA (Adami et al., 2022), SS (Zhang, T.P. et al.,2022), IBD (Opstelten et al., 2016), SLE (Bernatsky et al., 2011; Stojan et al., 2020; Yariwake et al., 2021), MN (Zhou et al., 2022)	PM10 activates PI3K/Akt/FOXO3a pathway (Liu, X. et al., 2022); PM2.5 induces PI3K/Akt/mTOR pathway (Zhang, F. et al., 2020a).
	Silica	SLE (Cooper et al., 2010; Sanchez-Roman et al., 1993), RA (McDermott and Sparks, 2023; Prisco et al., 2020; Vega Miranda et al., 2014), SS (Sanchez-Roman et al.,1993; Vega Miranda et al., 2014; Yi et al., 2016), sarcoidosis (Vega Miranda et al., 2014), SSc (Vega Miranda et al., 2014; Yi et al., 2016)	Silica particles activate PI3K/Akt pathway, leading to c-Src phosphorylation and subsequent expression of TGF-β1 (Hao et al., 2023).
	Cigarette Smoking	SLE (Barbhaiya et al., 2018; Chen, J. et al., 2022b; Fava and Petri, 2019; Majka and Holers, 2006), RA (McDermott and Sparks, 2023; Pisetsky, 2023; Prisco et al., 2020), MS (Olsson et al., 2017), GD (Aranyosi et al., 2022; Bartalena et al., 2020; Ferrari et al., 2017; Kau et al., 2016), PBC (Gershwin et al., 2005; Rutledge and Asgharpour, 2020), FMS (Bokarewa et al., 2014; Orhurhu et al., 2015)	Nicotine and tobacco carcinogen in cigarette smoke rapidly activate Akt (West et al., 2003).
	Noise	NIHL (Fan et al., 2023; Wang et al., 2020; Zhang, A. et al., 2020), IBD (Zhang, A. et al., 2020)	Noise exposure inhibits the PI signaling pathway and decreases the levels of phosphorylated PI3K and Akt (Fan et al., 2023).
Chemical Pollution	PAHs	RA (Tamaki et al., 2004; Ye et al., 2022), SLE (Gilcrease et al., 2020; Yu et al., 2022; Zhu et al., 2023, T1D (Yu et al., 2022), MS (Yu et al., 2022)	PAH metabolites mutate p53, which amplifies nuclear PI signaling and Akt activation (Chen, M. et al., 2022; Choi et al., 2019; Pan et al., 2020; Shen et al., 2006); PAH metabolites target AhR and leads to induced PI3K/Akt signaling (Therachiyil et al., 2022) and sequential TNF-α and IL-6 expression (Guo et al.,2021).
	TCDD	AIH (Cannon et al., 2022), RA (Tamaki et al., 2004), SS (Ishimaru et al., 2009)	TCDD targets AhR and leads to induced PI3K-Akt pathway (Davis et al., 2000; Therachiyil et al., 2022).
	TCE	AIH (Wang, et al.,2014; Wang, et al.,2019), SLE (Wang, G. et al., 2014; Wang, H. et al., 2019), SSc (Wang, G. et al.,2014)	TCE exposure increases Akt phosphorylation, and the inhibition of Akt blocks the TCE-induced cell proliferation (Xia et al., 2022).
	Mercury	SLE (Barbhaiya and Costenbader, 2016; Crowe et al., 2015; Fava and Petri, 2019), HT (Benvenga et al., 2022; Pamphlett et al., 2021), MS (Anglen et al., 2015)	Mercury exposure leads to an increase in PI3K/Akt signaling (Chen et al., 2006).
	Cadmium	RA (Joo et al., 2019)	Cadmium exposure activates PI3K/Akt/mTOR signaling axis (Kulkarni et al., 2020).
Biological Pollution	EBV	SLE (Barbhaiya et al., 2018; Chen, J. et al., 2022b; Fava and Petri, 2019; Jog and James, 2020; Majka and Holers, 2006), MS (Bjornevik et al., 2022; Lanz et al., 2022; Olsson et al., 2017; Soldan and Lieberman, 2023), SSc (Farina et al., 2017), RA (Fadlallah et al., 2021; Kroos et al., 2022; Svendsen et al., 2021), APS (Kwok et al., 2022; Ogawa et al., 2002), SS (Drozdzik et al., 2014; Inoue et al., 2012)	EBV infection activates PI4K (Suzuki et al., 1992); EBNA1 induces PI4K and PIPK activity, leading to increased PtdIns4P and PtdIns(4,5)P2 (Suzuki et al., 1992); EBV latent proteins LMP1 and LMP2A activate the PI3K/Akt pathway and enhance the activity of IRF4 (Luo et al., 2021; Wang, L. et al., 2017); LMP1 downregulates the expression of PTEN by increasing the expression of miR-21 to amplify PI3K/Akt signaling (Yang et al., 2016); EBV-miRNA-BART7-3P contributes to the PI3K/Akt signaling through PTEN inhibition (Luo et al., 2021); EBV envelope protein gp350 binds CR2/CD21 receptor to activate PI3K (D’Addario et al., 1999; Pan et al., 1996).
	H. pylori	IBD (Lord et al., 2018), ITP (Vanegas and Vishnu, 2019), PBC (Goo et al., 2008), RA (Zentilin et al., 2002), SLE (Wu et al., 2020)	H. pylori infection inhibits platelet autophagy through the phosphorylation and inactivation of PTEN (Suzuki et al., 2009; Zhu et al., 2008).
	C. albicans	Psoriasis (Whitley et al., 2022), T1D (Soyucen et al., 2014), IBD (Gerard et al., 2015)	C. albicans infection activates PI3K/Akt/mTORC1 signaling pathway (Shi et al., 2011); mTORC1 increases the phosphorylation level of STAT3 and promotes the differentiation (Delgoffe et al., 2011).
	Pollen	IBD (Johnson et al., 2019), SLE (Jimenez-Alonso et al., 2004), ITP (Ring et al., 2009), sarcoidosis (Van Gundy and Sharma, 1987)	Pollen exposure activates PI3K/Akt signaling pathway (Kampe et al., 2012); p-Akt enhances the phosphorylation and degradation of IκB-α , and leads to the activation of NF-κB and upregulation of TNF-α (Shimamura et al., 2003).

Table 2.

Association between Autoimmune Diseases and PI Signaling.

Autoimmune Diseases	Involved Phosphoinositide Signaling
Systemic Lupus Erythematosus (SLE)	Inhibition of PI3Kδ and PI3Kγ reduces macrophage kidney infiltration and ameliorates systemic lupus (Barber et al., 2005; Suarez-Fueyo et al., 2014).
	Inhibition of the PI3K/Akt/mTOR signaling pathway mitigates the inflammatory response and alleviates SLE (Bacalao and Satterthwaite, 2020; Dong et al., 2023).
Rheumatoid Arthritis (RA)	Suppression of PDK1-induced Akt activation and RSK2 phosphorylation inhibits migration and invasion of RA-FLS (Ma et al., 2019).
	Activation of the PI3K/Akt signaling pathway regulates anti-apoptotic properties and inflammatory cytokines production in RA-FLS (Aihaiti et al., 2021).
	Inhibition of PI3Kγ reduces late-stage joint-specific inflammation in collagen-induced arthritis (CIA) (Camps et al., 2005).
	Activation of the PI3K/Akt/mTOR/SREBP1/SCD-1 axis reduces ferroptosis of synovial fibroblasts in RA (Cheng et al., 2022).
	Inhibition of the PI3K/Akt/mTOR/HIF-1α pathway interrupts angiogenesis in RA (Ba et al., 2021).
Sjögren’s Syndrome (SS)	Inhibition of the PI3K/Akt/mTOR pathway improves the inflammatory microenvironment and relieves SS symptoms (Zeng et al., 2022a; Zeng et al., 2022b).
Systemic Sclerosis (SSc)	Inhibition of the PI3K/Akt pathway may mediate the role of calpain in macrophage polarization toward the M1 phenotype in bleomycin model of SSc-ILD (Zhang, L. et al., 2022).
	Regulating FAK/PI3K/Akt signaling pathway via integrins effectively attenuates skin fibrosis (Huang, Y. et al., 2023).
Antiphospholipid Syndrome (APS)	The PI3K/Akt signaling pathway negatively regulates autophagy by mediating the mTOR expression in endothelial cells (Zhang et al., 2021).
Fibromyalgia Syndrome (FMS)	Phosphorylation of the PI3K/Akt/mTOR/NF-κB signaling pathway is increased in the mouse thalamus and SSC after inducing FM (Chen et al., 2019).
Inflammatory Bowel Disease (IBD)	Inhibition of the PI3K/Akt/mTOR signaling pathway promotes autophagy in IECs and limits colonic inflammation (Chen, S.L. et al., 2023; Larabi et al., 2020; Zhao et al., 2015).
Multiple Sclerosis (MS)	Increased phosphorylation of various proteins in the PI3K/Akt/mTOR pathway potentially enhances Oligodendrocyte progenitor (OLP) cell proliferation, reduces apoptosis, and enhances myelination (Kumar et al., 2013).
	PI3K serves as the critical signaling mediator of CD28, regulating cell metabolism and amplifying specific inflammatory T cell phenotypes in MS (Kunkl et al., 2019).
Graves’ Disease (GD)	OPN activates OFs and induces VEGF and collagen I mRNA expression in OFs through the PI3K/Akt signaling pathway (Lou et al., 2021).
	TSHR signaling in TED OFs stimulates cell proliferation directly through PI3K/Akt signaling pathway (Woeller et al., 2019).
	Activation of the PI3K/Akt/mTOR pathway promotes the expression of GT1b-induced HAS2 (Yoo et al., 2021).
	Inhibition of phosphorylation and activation of the PI3K/Akt signaling pathways promotes cell apoptosis and GD remission (Xin et al., 2021).
Hashimoto’s Thyroiditis (HT)	High expression of the PIK3CG gene may play a role in PI3K mediated signaling in HT (Gan et al., 2021; Li, H. et al., 2018; Wojciechowska-Durczynska et al., 2012).
Autoimmune Hepatitis (AIH)	CCN1 stimulates IL-6 production via α6β1/PI3K/AKT/NF-κB signaling pathway in the pathogenesis of AIH (Jiang et al., 2022).
	Suppressing the activation of PI3K/Akt pathway relieves inflammation and fibrosis in AIH (Huang, Z. et al., 2023; Wang, S. et al., 2022).
	inhibiting GRK2 translocation mediated PI3K/Akt/mTOR signaling modulates lipid metabolism in T lymphocytes of AIH (Jin et al., 2022).
Primary Biliary Cirrhosis (PBC)	Up-regulating the PI3K/Akt signaling activates HSCs in liver fibrosis (Ma et al., 2017).
Type 1 Diabetes (T1D)	Dysregulation of the insulin/PI3K/Akt pathway is implicated in diabetes (Guastafierro et al., 2017).
	Diabetic BMDMs exhibit impaired PI3K expression with lower p-PI3K p55 levels and higher levels of PI3K p110α (Galvao Tessaro et al., 2020).
	Over-expression of the PI3Kδ isoform mediates increased Ca2+ current through CaV1.2 channels, driving increased contractility in diabetic vessels (Pinho et al., 2010).
Membranous Nephropathy (MN)	Inhibiting PI3K/Akt signaling activates renal autophagy, reducing cell proliferation and inflammation in MN (Chen, J. et al., 2022a).
Sarcoidosis	Both downregulation and upregulation of the PI3K/Akt signaling pathway have been associated with sarcoidosis (Konigsberg et al., 2023).
	Activation of PI3K relates to the upregulation of apoptotic, immune response and development pathways in sarcoidosis patients (Vukmirovic et al., 2021).
	Inhibition of programmed death impairs CD4+ T cell proliferation in Sarcoidosis by inhibiting the PI3K/Akt/mTOR signaling pathway (Celada et al., 2017).
Psoriasis	mTORC1 increases the expression of HIF-1α and positively regulates Th17 differentiation by enhancing Th17-related gene expression (Shi et al., 2011).
	Activating PI3K/Akt/mTORC1 signaling pathway increases the phosphorylation level of STAT3, resulting in the differentiation of Th17 cells and the expression of related cytokine IL-17, and leading to the release of IL-6, IL-1β and TNF-α (Chen et al.,2021).
Vitiligo	High expression of PTEN in the skin junction between normal and lesional areas of vitiligo leads to the inhibition of Akt phosphorylation at S473 (Zhu et al., 2020).
	Impaired activation of Akt is observed in vitiligo lesions (Kim et al., 2007; Kim and Lee, 2010).
Immune Thrombocytopenic Purpura (ITP)	PTEN inhibits PI3K/Akt/mTOR signaling pathway, thereby enhancing the expression of autophagy-related proteins, inhibiting cell apoptosis and improving platelet viability (Guo et al., 2015; Wang, C.Y. et al., 2019).
Noise-Induced Hearing Loss (NIHL)	Activation of the PI3K/Akt signaling pathway provides protection against NIHL (Chen et al., 2015; Fan et al., 2023).

2. IMPACT OF PHYSICAL POLLUTANT-INDUCED PI SIGNALING ON AUTOIMMUNE DISEASES

Physical pollution refers to the introduction of materials or objects into the environment that can lead to toxicity or harm. This category encompasses various factors, including but not limited to ultraviolet (UV) radiation, particulate matter (PM), silica, cigarette smoking, and noise. In the subsequent section, we delve into their effects on PI signaling within the context of autoimmunity, exploring the role of physical environmental stress-induced lipid signaling in immune disorders.

2.1. UV

Radiation exists all around us, from both natural and manmade sources, and is in two forms: ionizing and non-ionizing radiation. UV radiation, a form of non-ionizing radiation, in the context of pervasive environmental exposure to electromagnetic radiation from the sun, has the potential to cause severe skin damage especially for sensitive populations (Wolf et al., 2018). Notably, sensitivity to UV light is a characteristic shared among various autoimmune diseases such as SLE (Cooper et al., 2010; Fava and Petri, 2019; Garcia-Romo et al., 2011; Lood et al., 2016; Wolf et al., 2018), RA (Alex et al., 2020; Arkema et al., 2013), and vitiligo (Baldini et al., 2017; Le Poole, 2021; Wan et al., 2017). While the biological mechanisms of autoimmune photosensitivity are not fully understood, they may involve UV-driven DNA damage, apoptosis, autoantigen exposure, cytokine production, inflammatory cell recruitment, and systemic flare induction (Wolf et al., 2018). Significant for many of these processes (Patel and Mohan, 2005), phosphoinositide signaling is activated as a stress response to UV radiation (Chen et al., 2020; Strozyk and Kulms, 2013) and has reported links to SLE (Barbhaiya et al., 2022; Bijl and Kallenberg, 2006), RA (Ding, Q. et al., 2023), and vitiligo (Teng et al., 2021). This overlapping relevance suggests PI signaling may operate at the intersection of UV-driven repercussions and the associated autoimmune responses. For instance, UV exposure can potentially trigger the onset of SLE in susceptible females leading to the appearance of a malar rash (Barbhaiya et al., 2022). In individuals with active SLE, blood lymphocytes express relatively higher levels of the p53 protein (Miret et al., 2003), which has been shown to be a novel effector of PIP_ns (Chen, M. et al., 2022; Choi et al., 2019). Upon UV radiation, p53 and nuclear PI signaling components PtdIns4P, PtdIns(4,5)P₂, PtdIns(3,4,5)P₃, and a nuclear PI3K, inositol polyphosphate multikinase (IPMK), are rapidly assembled at the DNA damage sites (Wang, Y.H. et al., 2017; Wang, Y.H. et al., 2022). Our recent studies demonstrated that stress-induced p53 binds with PtdIns(4,5)P₂ which recruits small heat shock proteins for stabilization (Choi et al., 2019). The p53-PtdIns(4,5)P₂ complex is further processed by IPMK into p53-PtdIns(3,4,5)P₃ resulting in nuclear Akt activation and stress resistance (Chen, M. et al., 2022). Meanwhile, increased PI3K activity has been reported in SLE, leading to the activation of the PtdIns(3,4,5)P₃/Akt/mechanistic target of rapamycin (mTOR) cascade (Pan et al., 2020). This cascade, in turn, stimulates the synthesis of proteins involved in cellular division, proliferation, and lymphocyte survival (Pan et al., 2020). The relationship between UV radiation, PI signaling, and autoimmune responses appears to be intricately intertwined (Fig. 4). As a result, targeting the phosphoinositide signaling pathway shows promise in managing autoimmune photosensitivity.

Fig. 4.

Proposed model of UV radiation-induced PI signaling in SLE. Upon UV radiation, p53 and nuclear PI signaling components PtsIns4P, PtdIns(4,5)P₂, PtdIns(3,4,5)P₃, and a nuclear PI3K IPMK are rapidly assembled in the DNA damage sites. Additionally, p53 facilitates the activation of nuclear Akt through the presentation of PtdIns(3,4,5)P₃. Activation of the PI3K/Akt signaling pathway can stimulate lymphocyte activation and subsequent inflammation, potentially contributing to the development of SLE. The diagram is generated using BioRender.

2.2. PM

PM most commonly refers to fine solid or liquid particles suspended in the air, primarily from the daily use of fuels in appliances without emissions abatement systems, industrial emissions, and vehicular traffic (Izzotti et al., 2022). PM pollution, especially PM₁₀ and PM_2.5, is one of the major global public health concerns in large part because of its association with an increased risk for autoimmune diseases, such as RA (Adami et al., 2022), Sjögren’s syndrome (SS) (Zhang, T.P. et al., 2022), IBD (Opstelten et al., 2016), SLE (Bernatsky et al., 2011; Stojan et al., 2020; Yariwake et al., 2021), and membranous nephropathy (MN) (Zhou et al., 2022). Previous reviews have outlined the primary pathogenic mechanisms of PM, highlighting oxidative stress (Feng et al., 2016; Weichenthal et al., 2013; You et al., 2022), inflammation (Feng et al., 2016), apoptosis (Adami et al., 2022; Chen, Y. et al., 2023; Wang et al., 2021), autophagy (Chen, Y. et al., 2023; Wang et al., 2021), and DNA damage (Liu, X. et al., 2022) as the main mechanisms leading to its adverse effects (Li, T. et al., 2022). Since PM pollutants could activate PI3K/Akt pathway (Garcia-Cuellar et al., 2020; Zhang, F. et al., 2020a), PI signaling may participate in these pathogenic mechanisms and play a significant role in the occurrence and development of RA (Ba et al., 2021), SS (Zeng et al., 2022a; Zeng et al., 2022b), IBD (Chen, S.L. et al., 2023; Larabi et al., 2020), SLE (Suarez-Fueyo et al., 2014), and MN (Chiou et al., 2021). For example, ingestion of PM, one common route of exposure, can directly impact epithelial cells, inducing proinflammatory responses and increasing gut permeability (Beamish et al., 2011). In IBD, upregulated colonic glial-derived neurotrophic factor (GDNF) has been shown to have anti-apoptotic properties in colonic epithelial cells through the activation of the PI3K/Akt signaling pathway, contributing to chronic inflammation and affecting intestinal epithelial barrier/integrity (Steinkamp et al., 2003). Additionally, the PI3K/Akt/mTOR signaling pathway is involved in the pathogenesis of IBD through the regulation of autophagy (Jiang et al., 2019; Zhao et al., 2015). Inhibition of the PI3K/Akt/mTOR pathway has been shown to promote autophagy in intestinal epithelial cells and exhibit a protective role in ulcerative colitis (UC) (Zhang, F. et al.,2020b). Considering the increasing prevalence of exposure to PM pollution, strengthening personal protection is a practical approach to safeguard the autoimmune system. Further research on the PI signaling pathway in the context of autoimmunity will provide new insights for preventing and treating PM-induced autoimmune diseases.

2.3. Silica

Silica (or silicon dioxide, SiO2) is a highly prevalent environmental component which mainly exists as polymorph quartz, cristobalite and tridymite in rocks, sand, and soil (Cavalin et al., 2022). While silica is considered an important trace element and has predominantly natural origins compared to other pollutants discussed here, it has been found to be remarkably deleterious to human health (Bai et al., 2023). Numerous studies have established links between silica and serious lung diseases, as well as systemic autoimmune diseases such as systemic sclerosis (SSc) (Vega Miranda et al., 2014; Yi et al., 2016), RA (McDermott and Sparks, 2023; Prisco et al., 2020; Vega Miranda et al., 2014), SLE (Cooper et al., 2010; Sanchez-Roman et al., 1993), SS (Sanchez-Roman et al., 1993; Vega Miranda et al., 2014; Yi et al., 2016), and sarcoidosis (Vega Miranda et al., 2014). Silica may facilitate the onset of autoimmune diseases by causing cell death, such as apoptosis (Gambelli et al., 2004), stimulating the polarization and pyroptosis of macrophages (Bierschenk et al., 2023; Lescoat et al., 2020), as well as cytokine secretion (Lafyatis and York, 2009). Previous studies have demonstrated the involvement of the PI3K/Akt signaling axis in these cellular processes, playing a critical role in developing the aforementioned diseases (Aihaiti et al., 2021; Zhang, L. et al., 2022). Indeed, silica particles activate the PI3K/Akt pathway, leading to c-Src phosphorylation and subsequent expression of transforming growth factor-beta 1 (TGF-β1) (Hao et al., 2023). SSc is a systemic autoimmune disease, characterized by immune system activation, fibrosis of skin and vasculopathy, and accompanied with various complications in internal organs (Gabrielli et al., 2009), particularly lung fibrosis (Yi et al., 2016; Zhang, L. et al., 2022). It has been demonstrated that calpains have an inhibitory role in the regulation of the PI3K/Akt pathway activity (Beltran et al., 2011). Indeed, pharmacological inhibition of calpain increases the protein levels of PI3K and subsequent Akt activation in lung tissues of the bleomycin model of SSc-ILD mice (Zhang, L. et al., 2022). As the PI3K/Akt signaling axis has been associated with macrophage polarization, it is plausible that inhibiting the PI3K/Akt pathway may mediate the role of calpains in promoting macrophage M1 polarization and regulating bleomycin-induced pulmonary fibrosis in mice (Tan et al., 2017). The complex connections between silica, PI signaling, and autoimmune diseases highlight the potential significance of targeting the PI pathways for treating silica-induced autoimmune disorders.

2.4. Cigarette Smoking

Cigarette smoking is an addictive behavior and is recognized as the primary risk factor for many chronic diseases (Ding, R. et al., 2023; Jiang and Alfredsson, 2020). It is firmly established as a significant public health concern, representing a complex environmental pollutant that encompasses both physical and chemical dimensions which cooperatively contribute to its environmental impact (Qiu et al., 2017; Wu, W. et al., 2022). The combustion of tobacco releases visible particulate matter, toxic chemicals, and harmful substances that give rise to various health issues including well-documented conditions such as lung cancer (Cheng et al., 2023) and multiple organ diseases (Kamimura et al., 2018; Larsson and Burgess, 2022). Moreover, smoking has been linked to negative impacts on mental health (Pham et al., 2020) and has been shown to trigger adaptive immunity, leading to the development of autoimmune diseases such as RA (McDermott and Sparks, 2023; Pisetsky, 2023; Prisco et al., 2020), SLE (Barbhaiya et al., 2018; Chen, J. et al., 2022b; Ekblom-Kullberg et al., 2014; Fava and Petri, 2019; Majka and Holers, 2006), MS (Olsson et al., 2017), Graves’ disease (GD) (Aranyosi et al., 2022; Bartalena et al., 2020; Ferrari et al., 2017; Kau et al., 2016), primary biliary cirrhosis (PBC) (Gershwin et al., 2005; Rutledge and Asgharpour, 2020), and fibromyalgia syndrome (FMS) (Bokarewa et al., 2014; Orhurhu et al., 2015). Cigarette smoking contributes to the development of autoimmune diseases through several mechanisms, including cell apoptosis (Dang et al., 2020), autophagy (Yoshida et al., 2019), oxidative stress (Dang et al., 2020; Lugg et al., 2022; Perricone et al., 2016), macrophage polarization (Lugg et al., 2022; Mu et al., 2018), cytokines expression (Rodriguez-Rabassa et al., 2018; van der Vaart et al., 2005; Yang and Chen, 2018), and chronic inflammation (Polverino et al., 2021; Sparks and Karlson, 2016), among others. PI signaling, which is rapidly activated by nicotine and tobacco carcinogen in cigarette smoke (West et al., 2003), plays an important role in these smoking-induced pathological processes. A paradigmatic example is found in RA, where cigarette smoking represents the most well-recognized risk factor (Klareskog et al., 2010). RA is a systemic autoimmune disease involving chronic synovial inflammation as the main pathological feature (Cheng et al., 2022) and where angiogenesis in the synovial tissue is considered an important early event in its development (Elshabrawy et al., 2015). PI3K/Akt signaling activates mTOR to upregulate the expression of hypoxia-inducible factor-1α (HIF-1α) which is stabilized under inflammatory or hypoxic environments and quickly translocated to the nucleus. Once there, HIF-1α induces the expression of vascular endothelial growth factor (VEGF), promoting angiogenesis in the synovial tissue (Ferrara, 2004; Latacz et al., 2020). The PI3K/Akt signaling pathway is involved in the expression of various inflammatory factors during the pathogenesis of RA (Wu, N. et al., 2022). These inflammatory factors form a complex network, interact, influence each other, and ultimately directly or indirectly regulate the expression of VEGF thereby promoting inflammation and synovial pannus formation (Wu, N. et al., 2022). Furthermore, lysosomal-associated protein transmembrane 4B (LAPTM4B), identified as a pathogenic protein associated with smoking-induced lung diseases, acts as a PtdIns(4,5)P₂ effector, regulating epidermal growth factor receptor (EGFR) signaling (Tan et al., 2015a). EGFR activates the PI3K/Akt/mTOR pathway, which inhibits autophagy and may be linked to the aggravation of synovial inflammatory responses and the exacerbation of RA (Han et al., 2020; Tan et al., 2015b). Consequently, interrupting the PI3K/Akt/mTOR/HIF-1α pathway to reduce angiogenesis in synovial tissue may offer an effective strategy for impeding the progression of RA (Ba et al., 2021). Cigarette smoking affects the progression of autoimmune diseases through various pathways, however, PI signaling has emerged as a significant player. Therefore, further research on PI signaling holds promise in identifying potential therapeutic targets for the treatment of autoimmune diseases like RA.

2.5. Noise

Noise is a widely existing stressor in daily life that can cause surprisingly significant alterations to the immune system and has been connected to several physical and mental disorders (Hahad et al., 2019). Prolonged exposure to high levels of noise can lead to hearing loss, stress, sleep disturbances, and other problems (Zaman et al., 2022). Many studies have shown that noise may also play a vital role in the occurrence and progression of certain autoimmune diseases, such as noise-induced hearing loss (NIHL) (Fan et al., 2023; Wang et al., 2020; Zhang, A. et al., 2020) and IBD (Zhang, A. et al., 2020). There is substantial evidence suggesting that noise not only participates in hearing defects via affecting the function of hair cells in the cochlea but can also influences multiple systems and suffices to induce changes in the immune system (Carlson and Neitzel, 2018; Zhang, A. et al., 2020). NIHL is a prominent example of the negative impact of excessive noise exposure (Gupta and Sataloff, 2003). Research in the past decade has focused on the role of the PI3K/Akt signaling pathway in maintaining the integrity of cochlear hair cells and their protection mechanisms under stress conditions like noise (Jadali et al., 2017; Kucharava et al., 2019). Studies have shown that noise exposure inhibited the PI signaling pathway and decreased the levels of phosphorylated PI3K and Akt. Consistently, when phosphatase and tensin homolog (PTEN) is knocked down, the activity of the PI3K/Akt pathway increases, providing protection against cochlear hair cell loss (Fan et al., 2023). Furthermore, noise-induced sleep disorders have been found to increase the levels of cytokines such as interleukin (IL)-1, IL-17 and tumor necrosis factor α (TNF-α) (Irwin, 2019). Elevated levels of these cytokines are associated with a variety of autoimmune diseases, including IBD, as they promote the production of specific autoantibodies (Hsiao et al., 2015). The underlying pathological mechanisms of noise-induced autoimmune diseases still requires additional attention. Targeting the activation of the PI signaling pathway may offer a new approach for the development of effective pharmacological interventions in the context of these conditions.

3. IMPACT OF CHEMICAL POLLUTANT-INDUCED PI SIGNALING ON AUTOIMMUNE DISEASES

A chemical environmental pollutant is a harmful substance or compound released into the environment that can have adverse effects on ecosystems, human health, and other living organisms due to its toxic or damaging chemical properties. In the following section, we discuss five representative types of chemical environmental pollutants and examine their impacts on PI signaling within the context of autoimmunity, highlighting the significance of chemical environmental stress-induced lipid signaling in immune disorders.

3.1. Polycyclic Aromatic Hydrocarbons (PAHs)

PAHs are a group of organic compounds commonly found in combustion processes. In modern societies, PAHs are derived mainly from vehicle traffic, industrial activities, cooking with wood or petroleum, and tobacco smoke (Cetin et al., 2018; Liu, Y. et al., 2015). As persistent pollutants, PAHs have been identified as toxicants capable of carcinogenic and immunotoxic effects (Senturk, 2013; Shukla et al., 2022). These environmental pollutants are associated with various autoimmune diseases, including RA (Tamaki et al., 2004; Ye et al., 2022), SLE (Gilcrease et al., 2020; Yu et al., 2022; Zhu et al., 2023), T1D (Yu et al., 2022), and MS (Yu et al., 2022). The mechanisms through which PAHs contribute to these diseases commonly involve DNA mutation, oxidative damage, T-cell activation, and cytokine secretion (Yu et al., 2022). PAHs must be metabolically transformed by a series of xenobiotic-metabolizing enzymes (XMEs) into more reactive metabolites. These metabolites can directly react with DNA and proteins to form adducts, leading to DNA mutations and altered protein functions (Moorthy et al., 2015). A more recent study has reported that PAH metabolites mutate p53 (Shen et al., 2006), a known regulator that amplifies nuclear PI signaling, activates Akt, and dysregulates lymphocytes as previous discussed (Chen, M. et al., 2022; Choi et al., 2019; Pan et al., 2020). This supports the connection between PAH exposure, PI signaling, and autoimmune responses. Additionally, PAH metabolites target a protein receptor named aryl hydrocarbon receptor (AhR) (Vondracek et al., 2020). The activation of AhR leads to induced PI3K-Akt signaling (Therachiyil et al., 2022). Consistently, inhibition of PI3K has been shown to alleviate the expression of inflammatory cytokines TNF-α and IL-6 induced by PAHs (Guo et al., 2021). Taking MS, the most common demyelinating and neurodegenerative diseases affecting the central nervous system (CNS) in young adults (Filippi et al., 2018), as one example, TNF and IL are major cytokines playing pivotal roles in pathogenesis and progression (Fiedler et al., 2017; Fresegna et al., 2020). PI3K/PDK1/Akt/mTOR signaling participates in pro-inflammatory cytokine levels, regulating cell metabolism, and amplifying specific inflammatory T cell phenotypes in MS (Kunkl et al., 2019; Park et al., 2009). Taken together, these connections indicate the mediating role of PI signaling in PAH-induced immune disorders (Fig. 5).

Fig. 5.

Proposed model of PAHs-induced PI signaling in MS. PAHs undergo metabolic transformation upon cellular entry, forming active metabolites. These metabolites can react with DNA and proteins, resulting in the formation of adducts that lead to DNA mutations and altered protein functions. PAH metabolites have the potential to induce mutations in the p53 gene, leading to enhanced nuclear PI signaling and activation of Akt. Additionally, PAH metabolites can target AhR, triggering the PI3K/Akt pathway and subsequent expression of inflammatory cytokines such as TNF-α and IL-6. The resulting inflammation may contribute to the development of MS. The diagram is generated using BioRender.

3.2. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)

TCDD, perhaps the most notorious pollutant, is an extremely toxic environmental contaminant belonging to the dioxin family (Gogal and Holladay, 2008). It is produced as a byproduct of chemical synthesis, including the manufacturing of certain chlorinated herbicides and fungicides. TCDD is also released during the combustion of chlorinated organic compounds and chlorine-based wood pulp bleaching (Sund et al., 1993). The adverse health effects associated with TCDD exposure range from cancer to reproductive and developmental abnormalities to dysfunction of the immune system (Bell et al., 2010; Canga et al., 1993; Mead, 2008; Peterson et al., 1993). TCDD has been shown to modulate the human immune system and mediate certain autoimmune diseases like autoimmune hepatitis (AIH) (Cannon et al., 2022), RA (Tamaki et al., 2004), and SS (Ishimaru et al., 2009) through triggering immune cell apoptosis, altering B/T cells subsets and functions, and regulating the expression of cytokines and co-stimulatory molecules (Camacho et al., 2005; Ito et al., 2002; Singh et al., 2008). Similar to PAH, TCDD also targets AhR and leads to induced PI3K-Akt signaling (Davis et al., 2000; Therachiyil et al., 2022), which may be implicated in the pathogenesis of these diseases. Sjögren’s syndrome is primarily considered a B/T cell-mediated autoimmune disorder characterized by lymphocyte infiltration, destruction of exocrine glands, especially salivary glands, and systemic production of autoantibodies (Fox, 2005; Fox et al., 2000; Kruize et al., 1995). Inhibition of phosphorylation events in the PI3K/Akt/mTOR pathway have been reported to decrease the secretion levels of inflammatory cytokines such as IL-17, alleviate the focal infiltration of lymphocytes, modulate the inflammatory microenvironment, and thus attenuate clinical symptoms and improve life quality for patients with SS (Zeng et al., 2022a; Zeng et al., 2022b). Studies have also demonstrated significant expression of phosphorylated ribosomal protein S6 (pS6), a downstream mediator of the PI3Kδ pathway, within the salivary glands. The prophylactic or therapeutic blocking of PI3K activity by seletalisib, a PI3Kδ selective inhibitor, has shown promise in significantly reducing the aggregation of lymphocytes and plasma cells in the salivary gland, thus improving clinical symptoms (Nayar et al., 2019). The immune system changes caused by TCDD exposure are interrelated to autoimmune diseases. Besides simple avoidance of environmental pollutants, exploring the connection between PI signaling pathways and TCDD-induced autoimmune diseases not only enhances our understanding of disease mechanisms but also holds the potential for developing effective treatments by targeting this pathway.

3.3. Trichloroethylene (TCE)

Chlorinated ethenes, including vinyl chloride (VC), dichloroethylene (DCE), perchloroethylene (PCE), and especially TCE, are commonly used as industrial solvents and degreasers in the chemical industry (Liu, S. et al., 2022). However, they are also pervasive environmental contaminants with adverse effects on ecosystems and human health through similar mechanisms (Anders et al., 2016; Chen et al., 2002; Liu, C. et al., 2015). TCE is perhaps the most relevant chlorinated ethene as it is classified as a primary carcinogen due to its asymmetric molecular structure and active chemical properties (Henschler et al., 1976; Kotik et al., 2013). In this section, we focus on TCE as a representative chlorinated ethane to explore its connection with PI signaling pathways and autoimmune diseases. Prolonged exposure to TCE through inhalation, ingestion, or skin contact can lead to a range of health issues, including certain cancers, liver and kidney damage, neurological effects, and autoimmune diseases (Cooper et al., 2009; Purdue, 2013; Wang et al., 2023). In recent years, many investigations of immune-related effects of TCE have been conducted, and part of this work focused on autoimmune diseases such as AIH, SLE, and SSc (Wang, G. et al., 2014; Wang, H. et al., 2019). Several biological mechanisms and pathways have been delineated in the pathogenesis of TCE-mediated autoimmune diseases, including systemic oxidative stress, apoptosis, autophagy, and inflammasome activation (Cooper et al., 2009; Wang et al., 2008; Wang, G. et al., 2019; Wang, H. et al., 2019). Like other environmental pollutants, the PI3K/Akt pathway plays a vital role in the cellular processes triggered by TCE. For instance, TCE exposure increases Akt phosphorylation, and the inhibition of Akt blocks TCE-induced cell proliferation (Xia et al., 2022). Activating α6β1/PI3K/Akt/nuclear factor-κB (NF-κB) signaling pathway may upregulate the production of specific cytokines, such as IL-6, and promote inflammation in AIH (Jiang et al., 2022). Conversely, suppressing the activation of the PI3K/Akt pathway and reducing the phosphorylation of Akt and PI3K have been suggested to significantly ameliorate hepatitis and liver fibrosis (Huang, Z. et al., 2023; Wang, S. et al., 2022). Similarly, activation of PI3K signaling contributes to exacerbating inflammation in SLE (Dong et al., 2023). In addition to TCE, other chlorinated ethenes, including VC (Anders et al., 2016), DCE (Chen et al., 2002), and PCE (Liu, C. et al., 2015), have been reported to be associated with PI signaling. Although the mechanisms underlying the connection to autoimmune diseases are not fully elucidated, future research directions may explore the potential therapeutic approaches involving the interference with PI signaling in chlorinated ethene-related autoimmune diseases.

3.4. Mercury

Mercury is a well-known heavy metal that is ubiquitous in the environment (Yang et al., 2020). It has the potential to cause toxic effects on the nervous, digestive, and immune systems, as well as various organs (Cappelletti et al., 2019; Paduraru et al., 2022). In severe cases of mercury intoxication, it can even lead to death (Pereira et al., 2019). Mercury exerts its impact on human health through several biological mechanisms, including cell apoptosis, autophagy, and oxidative stress (El Asar et al., 2019; Han et al., 2022; Zhao et al., 2021), leading to certain autoimmune diseases including SLE (Barbhaiya and Costenbader, 2016; Crowe et al., 2015; Fava and Petri, 2019), HT (Benvenga et al., 2022; Pamphlett et al., 2021), and MS (Anglen et al., 2015). Mercury is a widely recognized toxic metal that is known to induce oxidative stress (Chen et al., 2006). There is an emerging association between mercury exposure and stress responsive PI signaling. It has been observed that mercury exposure leads to an increase in PI3K activity, as well as the phosphorylation of its downstream effector, Akt (Chen et al., 2006). Studies have also demonstrated that exposure to mercury can induce autophagic cell death, which may be linked to the regulation of PI3K signaling cascades. The PI signaling pathway plays an important role in controlling the activation of inflammatory cells and the release of inflammatory transmitters during the chronic inflammatory response in HT (Gan et al., 2021; Li, H. et al., 2018). Luteolin and Kaempferol, reported PI3K/Akt signaling modulators, offer critical regulation against inflammation and show exciting potential in the treatment of HT (Gan et al., 2021). The relationship between mercury, PI signaling, and autoimmune responses seems to be convoluted. Overall, mercury’s association with autoimmune diseases and its influence on cellular processes, including the PI signaling pathway, requires further research for a comprehensive understanding. By deepening our knowledge of these connections, we can potentially develop targeted interventions to mitigate the adverse effects of mercury and improve treatment outcomes for autoimmune diseases.

3.5. Cadmium

Cadmium is a hazardous heavy metal found in industrial emissions, batteries, and certain fertilizers (He et al., 2022). Long-term exposure to cadmium can cause organ damage, increase the risk of cancer, and induce the occurrence of autoimmune diseases (Frangos and Maret, 2020). Cadmium exposure can exacerbate inflammatory responses in diseases through various pathways, including oxidative stress, DNA damage, and apoptosis (Ma et al., 2022; Yan and Allen, 2021). Studies have shown that cadmium plays a role in certain arthritic diseases, such as RA (Frangos and Maret, 2020; Joo et al., 2019), as an effector of the immune system, inflammation, and cellular metabolism. Specifically, inhalation of cadmium has been suggested as a trigger of a specific form of RA known as nodular RA (Murphy et al., 2019). The PI3K/Akt/mTOR signaling axis is reported to be the primary molecular pathway activated by cadmium exposure (Kulkarni et al., 2020) and may contribute to the cellular processes associated with RA and nodular RA. RA is characterized by systemic synovitis, resulting in joint destruction (Liu et al., 2021). Interestingly, evidence supports the role of pro-inflammatory cytokines in triggering the PI3K/Akt signaling pathway, which is responsible for immune-mediated inflammation in RA. Activation of this signaling pathway leads to the production of pro-inflammatory cytokines, further exacerbating the disease (Cheng et al., 2022; Liu et al., 2021). The research exploring the relationship between cadmium and autoimmune diseases is still limited, and more in-depth investigation is needed. A better understanding of the PI signaling pathway and its inhibitors in relation to these pathogenic mechanisms may help identify therapeutic targets and develop new drugs for cadmium-induced autoimmune diseases.

4. IMPACT OF BIOLOGICAL POLLUTANT-INDUCED PI SIGNALING ON AUTOIMMUNE DISEASES

Biological environmental pollutants encompass a diverse array of living organisms, such as bacteria, viruses, fungi, and other microorganisms, as well as larger species like insects and plants, that can have detrimental effects on ecosystems, human health, and other living organisms. In the upcoming section, we delve into the influence of selected biological environmental pollutants on PI signaling within the context of autoimmunity, covering one virus, one bacterium, one fungus, as well as plant-based pollen as examples. This exploration underscores the relevance of considering the role of biological environmental stress-induced lipid signaling in immune disorders and its potential implications for future studies and therapeutic strategies.

4.1. Epstein-Barr Virus (EBV)

EBV, the first human tumor virus to be identified (Soldan and Lieberman, 2023), is a widespread biological pollutant and establishes lifelong infection in more than 90% of adults worldwide (Shannon-Lowe and Rickinson, 2019) serving as a conditional pathogen once the equilibrium between the host and the virus is disrupted. EBV is also closely associated with multiple human cancers. Besides carcinomas derived from epithelial cells (nasopharyngeal carcinoma and gastric carcinoma), EBV is mainly linked to lymphomas derived from B cells and T cells (Luo et al., 2021), such as Burkitt lymphoma, Hodgkin lymphoma, NK/T-cell lymphoma, and posttransplant lymphoproliferative disorder (PTLD) indicating a deep connection with the immune system. Indeed, EBV profoundly affects the immune system with researchers revealing the presence of EBV antibodies in the plasma of patients with various autoimmune diseases, such as SLE (Barbhaiya et al., 2018; Chen,J. et al., 2022b; Fava and Petri, 2019; Jog and James, 2020; Majka and Holers, 2006), MS (Bjornevik et al., 2022; Lanz et al., 2022; Olsson et al., 2017; Soldan and Lieberman, 2023), SSc (Farina et al., 2017), RA (Fadlallah et al., 2021; Kroos et al., 2022; Svendsen et al., 2021), antiphospholipid syndrome (APS) (Kwok et al., 2022; Ogawa et al., 2002), and SS (Drozdzik et al., 2014; Inoue et al., 2012), suggesting that EBV may be an important factor in the progression of these diseases (Damania et al., 2022; Sausen et al., 2021). When the human immune surveillance fails, latent EBV can undergo reactivation, resulting in abnormal cell proliferation and pathogenesis. Efficient virus replication relies on the host PI metabolism, where phosphatidylinositol-4-kinase (PI4K) and PtdIns4P play important roles (Delang et al., 2012). During these processes, certain EBV-encoded latent proteins and miRNAs play notable roles as well. Following EBV infection, PI4K activity is significantly induced in B cells (Suzuki et al., 1992). Expression of a latent EBV protein called EBV nuclear antigen 1 (EBNA1) can induce PI4K and PI4P-kinase (PIPK) activity, leading to increased levels of PtdIns4P and PtdIns(4,5)P₂ (Suzuki et al., 1992). Additionally, two other EBV latent proteins, LMP1 and LMP2A, activate the PI3K/Akt signaling pathway and enhance the activity of interferon regulatory factor 4 (IRF4) (Luo et al., 2021; Wang, L. et al., 2017). IRF4 is known to be involved in the differentiation of B cells, T cells, and macrophages (Shaffer et al., 2009). Additionally, LMP1 downregulates the expression of the PI3-phosphatase, PTEN, by increasing the expression of miR-21 (Yang et al., 2016). This, in turn, amplifies the PI3K/Akt signaling pathway. Besides, EBV-miRNA-BART7-3P could also contribute to the PI3K/Akt signaling through PTEN inhibition (Luo et al., 2021). Additionally, EBV utilizes its envelope protein gp350 to bind CR2/CD21 receptor, modulating proinflammatory cytokines including IL-6, IL-1β, and TNF-α (D’Addario et al., 1999). NF-κB pathway activation in gp350-treated cells depends on PKC and PI3K, potentially regulating IL-1β gene expression (D’Addario et al., 1999; Pan et al., 1996). The involvement of PI3K in B lymphocyte activation is still under exploration (Bouillie et al., 1999). While limited, research suggests a link between EBV-induced inflammatory changes and the PI signaling pathway (D’Addario et al., 2000; Soldan and Lieberman, 2023). Further investigation is needed to understand EBV’s role in autoimmune disorders and the PI signaling pathway (Fig. 6).

Fig. 6.

Proposed model of EBV-induced PI signaling in autoimmune diseases. Upon EBV infection, PI signaling is activated through multiple mechanisms. Firstly, the EBV protein EBNA1 induces the activity of PI4K and PIPK, resulting in elevated levels of PtdIns4P and PtdIns(4,5)P₂. Secondly, the EBV latent proteins LMP1 and LMP2A activate the PI3K/Akt pathway. LMP1 downregulates PTEN expression by upregulating miR-21, thereby amplifying PI3K/Akt signaling. Thirdly, EBV-miRNA-BART7-3P contributes to PI3K/Akt signaling by inhibiting PTEN. Furthermore, the EBV envelope protein gp350 binds to the CR2/CD21 receptor, activating PI3K. Induction of the PI3K/Akt pathway leads to the activation of Src and NF-κB, resulting in the release of various cytokines including IRF4, IL-6, IL-1β, and TNF-α. This inflammatory response may contribute to the development of autoimmune diseases. The diagram is generated using BioRender.

4.2. Helicobacter pylori (H. pylori)

H. pylori is a widely prevalent gram-negative microaerophilic bacterium, serving as a biological pollutant that colonizes the human stomach lining in more than half of the world’s population (Suerbaum and Michetti, 2002). Clinically, it is known to cause active chronic gastritis and is associated with various gastrointestinal disorders (Sharma et al., 2010). Infection with H. pylori is commonly linked to peptic ulcer disease, gastric cancer, and mucosa-associated lymphoid tissue (MALT) lymphomas, resulting in this bacterium being classified as a class I carcinogen by the World Health Organization (WHO) (Coats et al., 2003; Stasi and Provan, 2008). Chronic infection with H. pylori is considered as a source of persistent antigenic stimulation and underlies the causative agents’ ability to induce systemic inflammatory responses (Jackson et al., 2009). Studies have suggested a potential role for H. pylori in the development of various autoimmune diseases, including IBD (Lord et al., 2018), immune thrombocytopenic purpura (ITP) (Vanegas and Vishnu, 2019), PBC (Goo et al., 2008), RA (Zentilin et al., 2002), and SLE (Wu et al., 2020). H. pylori appears to participate in these diseases through multiple mechanisms, such as T/B cells activation and autophagy (Amedei et al., 2003; Ruan et al., 2023; Yamanishi et al., 2006). As early as 1998, researchers discovered a relevant connection between H. pylori infection and the onset of ITP (Gasbarrini et al., 1998). ITP is a complex autoimmune-mediated bleeding disease characterized by autoreactive antibodies produced due to immune dysregulation of T and B cells, resulting in decreased platelet production and/or increased platelet destruction (Shan et al., 2016). Studies have shown that PTEN protein expression is lower in all B cell subsets of ITP patients, excluding memory B cells, contributing to B cell hyper-responsiveness (Xie et al., 2018). Lower programmed death 1 (PD1) and PTEN protein expressions have also been observed in CD4⁺ T cells from ITP patients compared to healthy controls, leading to disturbances of CD4⁺ T - cell homeostasis (Zhao et al., 2019). Furthermore, platelet autophagy is believed to be regulated by PTEN in patients with ITP through the PI3K/Akt/mTOR signaling pathway. PTEN serves as a key positive regulator for autophagy, blocking the inhibitory effect of PI3K on autophagy and enhancing autophagy-related proteins in the PI3K/Akt/mTOR signaling pathway, thus inhibiting cell apoptosis, and improving platelet viability (Guo et al., 2015; Wang, C.Y. et al., 2019). However, genome sequencing results suggest that several genes, including PTEN, harbor an excess number of rare and damaging mutations in ITP patients, leading to the activation of the PI3K/Akt/mTOR pathway and inhibition of autophagy which plays an important role in the initiation and progression of ITP (Ruan et al., 2023). ITP triggered by the infection of H. pylori has been confirmed through various proposed mechanisms. A number of studies have shown a significant increase in platelet count of ITP patients upon eradication of H. pylori, which may also inhibit the production of antiplatelet autoantibodies and lead to alleviation or complete regression of the disease in many patients (Aljarad et al., 2018; Sheema et al., 2017). Interestingly, H. pylori infection has been suggested to phosphorylate and inactivate PTEN in vivo and in vitro (Suzuki et al., 2009; Zhu et al., 2008). Therefore, after long-term infection, in addition to generating cross-reactivity with platelet surface antigens in the presence of H. pylori cytotoxin-associated gene A (CagA), H. pylori may also inhibit platelet autophagy through phosphorylation and inactivation of PTEN thereby suppressing platelet destruction and shortening the lifespan of platelets in ITP patients. Considering the close association between H. pylori and ITP, every patient with unexplained thrombocytopenia should undergo an H. pylori test. Although there is no established mechanism to explain how H. pylori could be implicated in the pathogenesis of autoimmune diseases through influencing the PI3K/Akt signaling pathway, chronic infections and the persistent activation of the immune system might contribute to immune dysregulation, potentially affecting individuals with underlying autoimmune conditions. Thus, further study of the connection between H. pylori, PI signaling pathway and autoimmune diseases, as well as their role in the pathogenesis of autoimmune diseases, is warranted.

4.3. Candida albicans (C. albicans)

C. albicans is an opportunistic pathogen, acting as a biological pollutant that overgrows and leads to fungal infections of the mucosa and skin when the balance of microorganisms in the body is disrupted (Garber, 2001). In such cases, the immune system responds to the infection by mounting an inflammatory response. Some research suggests that chronic C. albicans infections may contribute to immune dysregulation, possibly influencing the development or exacerbation of autoimmune diseases in susceptible individuals, including psoriasis (Whitley et al., 2022), T1D (Soyucen et al., 2014), and IBD (Gerard et al., 2015). T helper 17 cells (Th17) play a crucial role in protecting against mucocutaneous C. albicans infection (Li, J. et al., 2018). Under the stimulation of C. albicans, CD4⁺ effector T cells can differentiate into Th17 cells that secrete cytokines such as IL-17A, IL-17F, and IL-22, with IL-23 promoting their own development and proliferation. These cytokines mediate protective immunity against fungi by promoting the recruitment of neutrophils and enhancing barrier functions (Li, J. et al., 2018; Whitley et al., 2022). The IL-23/IL-17/IL-22 inflammatory axis protects the human body through the antifungal immune response. However, if dysregulated, the IL-17 response can promote immune pathology of infection or autoimmune diseases, which may also contribute to C. albicans infection aggravating autoimmune diseases such as psoriasis (Sparber and LeibundGut-Landmann, 2019). Psoriasis is an immune-mediated chronic, recurrent, inflammatory, and systemic disease induced by the combined effects of an individual’s genetics and their environment (Rademaker et al., 2019). One of its typical characteristics is the excessive proliferation and abnormal apoptosis of keratinocytes (Nograles et al., 2010). Although the pathogenesis of psoriasis is not completely clear, it is currently believed that Th17 cells are abnormally activated and release a number of cytokines that act on keratinocytes and other subtypes of Th cells causing them to proliferate and secrete inflammatory factors while expressing some chemokines. These cytokines cooperate to sustain persistent inflammation, ultimately evolving into chronic inflammatory damage to the skin (Hawkes et al., 2018; Whitley et al., 2022). Numerous studies have shown that the PI signaling pathway is closely related to the function of T cells, and the PI3K/Akt/mTOR complex 1 (mTORC1) signaling pathway is mainly involved in the regulation of Th17 cells (Kurebayashi et al., 2021). mTORC1 is indirectly activated by Thr308-phosphorylated Akt. Thus far, several distinct mechanisms are believed to participate in the regulation of Th17 differentiation via mTORC1. One is the increased expression of HIF-1α, downstream of mTORC1, which positively regulates Th17 differentiation by enhancing Th17-related gene expression (Shi et al., 2011). In addition, activating the PI3K/Akt/mTORC1 signaling pathway can increase the phosphorylation level of signal transducers and activators of transcription 3 (STAT3), a transcription factor expressed in the nucleus of Th17 cells which promotes the differentiation of Th17 cells and the expression of related cytokines, including IL-17 (Delgoffe et al., 2011). IL-17A directly activates keratinocytes to express a variety of cytokines such as IL-6. It may also synergize with TNF-α to induce the release of IL-6, IL-1β, and TNF-α, thereby enhancing inflammatory actions and contributing to the deterioration of autoimmune diseases such as psoriasis (Chen et al., 2021). In conclusion, the activation of Th17 cells caused by C. albicans infection plays a predominantly antifungal role. However, under the regulation of PI3K signaling pathway, Th17 cells are also considered as the main participants in the pathogenesis of various autoimmune diseases due to the recruitment of neutrophils and the release of inflammatory factors. Therefore, prevention and treatment of C. albicans infection are effective measures to improve the symptoms of autoimmune diseases in this capacity. Moreover, an in-depth study of the relationship between C. albicans, the PI signaling pathway, and autoimmunity will help to identify new therapeutic targets for disease treatment.

4.4. Pollen

Pollen, the reproductive particle produced by plants, is a common biological environmental pollutant (Lara et al., 2023). Research has shown that the vast majority of pollen grains in humans do not reach the thoracic respiratory tract but are swallowed and come into direct contact with the mucosa of the digestive tract (Wilson et al., 1973). When inhaled or in contact with mucous membranes, pollen particles can activate the immune system, leading to the release of histamines and many other inflammatory mediators, thus triggering allergies in susceptible individuals (Buhner et al., 2023; Kampe et al., 2012). In some cases, continuous exposure to allergens such as pollen may contribute to immune dysregulation and aggravate autoimmune conditions in susceptible populations associated with autoimmune diseases including IBD (Johnson et al., 2019), SLE (Jimenez-Alonso et al., 2004), ITP (Ring et al., 2009), and sarcoidosis (Van Gundy and Sharma, 1987). Pollen grains themselves trigger local inflammation in the gastrointestinal mucosa, similar to their role in the nasal mucosa (Magnusson et al., 2003). Regarding IBD, pollen sensitization is often discussed as a potential factor in the pathogenesis process (Johnson et al., 2019). When exposed to pollen, the number of eosinophils in the peripheral blood increases significantly under the stimulation of allergens which can cause inflammatory actions in target tissues (Jedrzejczak-Czechowicz et al., 2011; Kampe et al., 2012). The intestinal mucosal barrier (IMB) is the first barrier against harsh environments, but it is disrupted in IBD patients (Wu et al., 2019). Studies have demonstrated that the number of eosinophils in the colonic mucosa of patients with IBD is significantly increased (Neubauer et al., 2018). Peripheral blood eosinophilia (PBE) is regarded as a biomarker of the aggressive multiyear natural history in adults with IBD (Prathapan et al., 2020). Eosinophils are multifunctional leukocytes participated in host defense and inflammatory response, as well as immune modulation. Once activated and recruited to the intestinal tissue, eosinophils secrete an array of inflammatory mediators and histotoxic granule proteins through degranulation, leading to tissue damage (Weller and Spencer, 2017). Pharmacological studies have found that the PI3K/Akt signaling pathway is involved in the regulation of eosinophils. Wortmannin, a PI3K inhibitor, specifically blocks PI3K and enhances cell apoptosis and autophagy. By inhibiting the PI3K/Akt signaling pathway, Wortmannin suppresses the proliferation, migration, and degranulation of eosinophils, decreases the release of inflammatory factors, and blocks the epithelial cell damage caused by inflammatory cytokines which may result in improving intestinal inflammation and protecting the IMB of patients with IBD (Huang et al., 2011; Lee, 2004). In addition to the influence of eosinophils, studies have confirmed that PI3K activation exists in the gastrointestinal mucosa of IBD patients. p-Akt enhances the phosphorylation and degradation of NF-κB inhibitory protein (mainly IκB-α), which may cause the activation of NF-κB and upregulation of TNF-α, thus sustaining and amplifying the inflammatory response (Shimamura et al., 2003). Ongoing exposure to allergens like pollen may lead to long-term hypersensitivity in susceptible individuals resulting in an imbalance in immune function which is likely to cause allergic diseases or autoimmune diseases. Although the involvement of pollen in the pathogenesis of autoimmune diseases is not yet well understood, inhibiting the PI3K/Akt pathway may be beneficial to alleviate the symptoms of the disease. Therefore, studying the role of PI signaling pathway in the pathogenic mechanisms of pollen is crucial for the treatment of the relevant autoimmune diseases.

5. CONCLUSION

In this study, we delve into the pivotal role of PI signaling in cellular responses to environmental contaminants within the context of autoimmune diseases. Understanding how PI signaling contributes to the initiation and progression of autoimmune diseases is essential for advancing our comprehension of the underlying pathological processes and for formulating effective prevention and treatment strategies. Environmental pollutants are categorized based on their physical, chemical, and biological nature, and their connections to specific autoimmune diseases are continuously being explored. Here, we have focused on discussing a few representative types of pollutants within each pollution category (Fig. 3). Each category encompasses additional pollutants not explicitly presented, and the list of pollutants associated with PI signaling and autoimmunity is expanding with growing scientific attention.

There are over 80 different types of autoimmune diseases, and each may have distinct factors contributing to their development (Rad et al., 2019). We acknowledge that autoimmune diseases can have diverse triggers and mechanisms, and not all of them may be directly related to PI signaling. However, it is crucial to note that the pollutants and autoimmune diseases we have examined bear notable implications for PI signaling (Table 1, 2), indicating a profound and fundamental relationship between PI signaling in the development of environmentally induced autoimmunity. Adding complexity to this relationship, pollutants from different sources may share common or even synergistic impacts on PI signaling. As shown in Table 1, both UV radiation and EBV influence PtdIns4P. Additionally, both UV radiation and PAHs affect the PI effector p53. Furthermore, it is noteworthy that all the listed environmental pollutants have an impact on the PI3K/Akt pathway. However, each pollutant may also exhibit specificity, necessitating further investigation.

Given the significance of PI signaling as a promising drug target, with a range of inhibitors and therapeutics available, future research endeavors could investigate the role of PI signaling in immune disorders related to environmental stress or assess the effectiveness of implementing PI signaling interventions using strategies that selectively target various PI kinases or lipid effectors, including PI4K (Li et al., 2021), PIPK (Semenas et al., 2014), PI3K (Sun and Meng, 2020), and Akt (Hua et al., 2021). Collectively, our review offers valuable insights for the development of interventions aimed at addressing immune disorders associated with environmental pollutants.

ENVIRONMENTAL IMPLICATION.

The review unveils significant environmental implications concerning PI signaling in autoimmune diseases. Through an examination of varied physical, chemical, and biological environmental pollutants, the study highlights the crucial role of stress-induced PI signaling in immune regulation and its intricate connection to the initiation of autoimmune disorders. The paper strongly emphasizes the pressing requirement to comprehend the intricate interplay between PI signaling pathways and environmental pollutants. These insights hold substantial importance for understanding autoimmune disease pathogenesis, paving the route for strategic approaches that can address their impact on both public health and the environment.

SYNOPSIS:

Phosphoinositide signaling at the intersection of environmental pollutants and autoimmunity provides novel insights for managing autoimmune diseases aggravated by pollutants.

HIGHLIGHTS:

• First reviewed environmental pollutants’ impact on PI signaling in autoimmunity.

• Responsible pollutants are grouped by physical, chemical, and biological origins.

• Exploring pollutant-responsive PI signaling in autoimmunity informs public health.

ABBREVIATIONS

AhR

aryl hydrocarbon receptor

AIH

autoimmune hepatitis

APS

antiphospholipid syndrome

C. albicans

Candida albicans

CagA

cytotoxin-associated gene A

CNS

central nervous system

DCE

dichloroethylene

EBNA1

EBV nuclear antigen 1

EBV

Epstein-Barr virus

EGFR

epidermal growth factor receptor

FMS

fibromyalgia syndrome

FOXO

forkhead box O

FYVE

Fab1, YOTB, Vac1, and EEA1

GD

Graves’ disease

GDNF

glial-derived neurotrophic factor

H. pylori

Helicobacter pylori

HIF-1α

hypoxia-inducible factor-1α

HT

Hashimoto’s thyroiditis

IBD

inflammatory bowel disease

IL-1

interleukin-1

IMB

intestinal mucosal barrier

IPMK

inositol polyphosphate multikinase

IRF4

interferon regulatory factor 4

ITP

immune thrombocytopenic purpura

LAPTM4B

lysosomal-associated protein transmembrane 4B

MALT

mucosa-associated lymphoid tissue

MN

membranous nephropathy

MS

multiple sclerosis

mTOR

mechanistic target of rapamycin

mTORC1

mTOR complex 1; mTORC2, mTOR complex 2

NF-κB

nuclear factor-κB

NIHL

noise-induced hearing loss

PAH

polycyclic aromatic hydrocarbon

PBC

primary biliary cirrhosis

PBE

peripheral blood eosinophilia

PCE

perchloroethylene

PD1

programmed death 1

PDK1

pyruvate dehydrogenase kinase isozyme 1

PH

pleckstrin homology

PI

phosphoinositide

PI3K

phosphoinositide 3-kinase

PIPK

PI4P-kinase

PIP_ns

polyphosphoinositides

PM

particulate matter

PtdIns

phosphatidylinositol

PTEN

phosphatase and tensin homolog

PTLD

posttransplant lymphoproliferative disorder

PX

phox homology

RA

rheumatoid arthritis

SiO₂

silicon dioxide

SLE

systemic lupus erythematosus

SS

Sjogren’s syndrome

SSc

systemic sclerosis

STAT3

signal transducers and activators of transcription 3

T1D

type 1 diabetes

TCDD

2,3,7,8-Tetrachlorodibenzo-p-dioxin

TCE

trichloroethylene

TGF-β1

transforming growth factor-beta 1

Th17

T helper cells 17

TNF-α

tumor necrosis factor-alpha

UC

ulcerative colitis

UV

ultraviolet

VC

vinyl chloride

VEGF

vascular endothelial growth factor

WHO

world health organization

XME

xenobiotic-metabolizing enzyme

DATA AVAILABILITY

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