Role of aryl hydrocarbon receptors in infection and inflammation

Abstract

The aryl hydrocarbon receptor (AhR) is a transcription factor that is activated by various ligands, including pollutants, microorganisms, and metabolic substances. It is expressed extensively in pulmonary and intestinal epithelial cells, where it contributes to barrier defense. The expression of AhR is pivotal in regulating the inflammatory response to microorganisms. However, dysregulated AhR expression can result in endocrine disorders, leading to immunotoxicity and potentially promoting the development of carcinoma. This review focuses on the crucial role of the AhR in facilitating and limiting the proliferation of pathogens, specifically in relation to the host cell type and the species of etiological agents involved in microbial pathogen infections. The activation of AhR is enhanced through the IDO1-AhR-IDO1 positive feedback loop, which is manipulated by viruses. AhR primarily promotes the infection of SARS-CoV-2 by inducing the expression of angiotensin-converting enzyme 2 (ACE2) and the secretion of pro-inflammatory cytokines. AhR also plays a significant role in regulating various types of T-cells, including CD4⁺ T cells and CD8⁺ T cells, in the context of pulmonary infections. The AhR pathway plays a crucial role in regulating immune responses within the respiratory and intestinal barriers when they are invaded by viruses, bacteria, parasites, and fungi. Additionally, we propose that targeting the agonist and antagonist of AhR signaling pathways could serve as a promising therapeutic approach for combating pathogen infections, especially in light of the growing prevalence of drug resistance to multiple antibiotics.

Keywords: AhR; bacteria; fungus; parasites; viruses.

Figure 1

The present study shows the interaction between tryptophan metabolites and the AhR in the context of SARS-CoV-2 infection. The accompanying illustration illustrates the mechanism by which the SARS-CoV-2 virus modulates tryptophan metabolism to enhance the production of AhR ligands, namely kynurenine (Kyn), indole 3 pyruvate (I3P), and serotonin. Notably, Kyn and I3P serve as ligands for AhR. The SARS-CoV-2-induced “cytokine storm” leads to an upregulation of pro-inflammatory cytokines, which in turn promotes Kyn production through the enzyme indoleamine 2,3-dioxygenase (IDO). Consequently, this indirect effect results in a reduction in melatonin production. Activation of the AhR enhances the induction of cytochrome P450 1B1 (CYP1B1), which in turn facilitates the conversion of melatonin to N-acetylserotonin (NAS). However, during SARS-CoV-2 infection, the levels of butyrate are suppressed due to the inhibition of butyrate’s histone deacetylase (HDAC) activity. Butyrate exerts its effects by reducing the activity of the pyruvate dehydrogenase complex (PDC), leading to the conversion of pyruvate to acetyl-CoA, which serves as a co-factor in the melatonergic pathway. According to research findings, it has been observed that vitamin D has the ability to up-regulate the expression of tryptophan hydroxylase (TPH) 2, resulting in an increased production of tryptophan (Try) and subsequently leading to an elevation in serotonin synthesis. Additionally, melatonin has the capacity to bind to the vitamin D receptor and subsequently enhance the transcriptional activity mediated by vitamin D. It is important to note that the red arrow signifies a positive effect, whereas the green arrow represents a negative effect.

Figure 2

The involvement of the AhR in influenza A virus (IAV) infection is of significant interest. Activation of AhR has been shown to influence the response of various cell types, potentially impacting the course of IAV infection. Notably, AhR not only affects the function and differentiation of CD4⁺ T cells during IAV infection, but also influences DNA methylation patterns in these cells. Similar mechanisms may be observed in CD8⁺ T cells. Furthermore, AhR presents a promising target for modulating T follicular helper (Tfh) cell responses, offering a potential avenue for therapeutic intervention. During infection with IVA, the AhR exerts a suppressive effect on the host’s immune responses by negatively regulating the function of dendritic cells (DCs) in their ability to prime naive CD8⁺ T cells. Consequently, this may lead to a reduction in the number of cytotoxic T lymphocytes (CTLs). Additionally, the AhR agonist, TCDD, enhances the expression of inducible nitric oxide synthase (iNOS) and promotes the recruitment of neutrophils in endothelial and respiratory epithelial cells, respectively. However, it is important to note that there exists a reciprocal inhibition between iNOS and neutrophils. ARNT interacts with the polymerase acidic (PA) protein, thereby exerting a significant influence on the viral pathogenicity of the influenza virus. The red arrow symbolizes a positive effect, whereas the green arrow signifies a negative effect.

Figure 3

Multiple mechanisms are involved in the regulation of AhR for maintaining gut microbiota homeostasis. One such mechanism involves the translocation of STING1 from the endoplasmic reticulum (ER) to the Golgi apparatus, followed by its subsequent movement into the nucleus through AhR and AhR ligands. The formation of the STING1-AhR complex requires the presence of positive regulators such as PML, which facilitate the expression of CYP1A1 and IL22. Indole-3-carboxaldehyde (IAld) and ICA, which are synthesized by L. gallinarum, have been found to suppress the expression of IDO1 and counteract the function of Kyn, consequently leading to a reduction in Foxp3⁺ transcription. This reduction in transcription may potentially hinder the differentiation of CD4⁺ Treg cells.