Effect of polycyclic aromatic hydrocarbons on immunity

Abstract

Nearly a quarter of the total number of deaths in the world are caused by unhealthy living or working environments. Therefore, we consider it significant to introduce the effect of a widely distributed component of air/water/food-source contaminants, polycyclic aromatic hydrocarbons (PAHs), on the human body, especially on immunity in this review. PAHs are a large class of organic compounds containing two or more benzene rings. PAH exposure could occur in most people through breath, smoke, food, and direct skin contact, resulting in both cellular immunosuppression and humoral immunosuppression. PAHs usually lead to the exacerbation of autoimmune diseases by regulating the balance of T helper cell 17 and regulatory T cells, and promoting type 2 immunity. However, the receptor of PAHs, aryl hydrocarbon receptor (AhR), appears to exhibit duality in the immune response, which seems to explain some seemingly opposite experimental results. In addition, PAH exposure was also able to exacerbate allergic reactions and regulate monocytes to a certain extent. The specific regulation mechanisms of immune system include the assistance of AhR, the activation of the CYP-ROS axis, the recruitment of intracellular calcium, and some epigenetic mechanisms. This review aims to summarize our current understanding on the impact of PAHs in the immune system and some related diseases such as cancer, autoimmune diseases (rheumatoid arthritis, type 1 diabetes, multiple sclerosis, and systemic lupus erythematosus), and allergic diseases (asthma and atopic dermatitis). Finally, we also propose future research directions for the prevention or treatment on environmental induced diseases.

Keywords: Autoimmune diseases; Immunity; Lymphocytes; Polycyclic aromatic hydrocarbons.

Fig. 1

Pathways of human exposure to polycyclic aromatic hydrocarbons (PAHs). PAHs enter the air primarily through volcanic eruptions, forest fires, coal burning, and automobile exhaust, and enter into the water through emissions from industry and sewage treatment plants, where they may sink to the seafloor. Airborne PAHs can exist in the gas phase or be adsorbed in suspended particulates in the air. PAHs also appear in soil, plants, and animals as the air and water circulate. PAHs in these environments can all contact humans in a variety of ways, including breathing the environmental and indoor polluted air, smoking or inhaling smoke from fireplaces, eating foods that contain PAHs, and direct exposure to contaminated soil. Occupational exposures can also occur when workers inhale exhaust fumes.

Fig. 2

The mechanisms of polycyclic aromatic hydrocarbons on human immune cells. PAHs contact mainly with the skin and respiratory tract, and tend to be concentrated in the skin and bronchial epithelial cells. Due to the high lipophilicity of PAHs, they readily penetrate the epithelial barrier, accumulate slowly in fat, and eventually persist for a long time. In general, AhR signaling is needed in both adaptive and innate immune cells, in addition to different intracellular mechanisms, including cytochrome P450 (CYP)- reactive oxygen species (ROS) axis and intracellular calcium mobilization. The study of epigenetic mechanisms has also become increasingly diverse. (1) PAHs can induce Th17 differentiation. The possible intracellular mechanisms include the Ahr-Jag1-Notch signaling pathway and the involvement of the glycogenesis regulator Hif-1α. The secretion of Th17 cytokines, including IL-17 and IL-22, was also increased. Th17 cells can be transformed by AhR into type 1 T regulatory (Tr1) cells that produce the immunosuppressive cytokine IL-10. Conversely, in Tr1 cells, IL-27 was able to increase the AhR expression through a Stat3-driven mechanism. (2) PAH exposure is associated with impaired Treg function, downregulation of Foxp3, and increased methylation in the Foxp3 promoter region. PM2.5 promotes the expression of Got1, resulting in hypermethylation of the Foxp3 locus, thereby inhibiting Treg differentiation. Changes in miR223 were also associated with lower Treg levels. (3) PAHs lead to increased expression of Th2-related markers and elevated levels of secreted IL-4 and IL-13. PAHs induce oxidative stress pathways that generate ROS. ROS production may also be caused by increased expression of p40phox, a member of the membrane NADPH oxidase complex. (4) PM up-regulated the level of CYP 1A1, thereby affecting the activation of human monocytes. CXCL8 production was induced, as was IL-1β secretion by monocytes and activated macrophages. (5) Exposure to PAHs results in enhanced mast cell signaling, degranulation, mediator and cytokine release, and allergic responses in vivo. Increased expression of several endoplasmic reticulum stress-related markers was also observed.