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

Keywords: Autoimmunity; Environmental pollutants; Phosphoinositide signaling.

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.

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.

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.

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.

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.

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.