Aryl Hydrocarbon Receptor Signaling Synergizes with TLR/NF-κB-Signaling for Induction of IL-22 Through Canonical and Non-Canonical AhR Pathways

Abstract

Interleukin 22 (IL-22) is critically involved in gut immunity and host defense and primarily produced by activated T cells. In different circumstances IL-22 may contribute to pathological conditions or act as a cancer promoting cytokine secreted by infiltrating immune cells. Here we show that bone marrow-derived macrophages (BMM) express and produce IL-22 after activation of the aryl hydrocarbon receptor (AhR) when cells are activated through the Toll-like receptor (TLR) family. The additional activation of AhR triggered a significant induction of IL-22 in TLR-activated BMM. Deletion and mutation constructs of the IL-22 promoter revealed that a consensus DRE and RelBAhRE binding element are necessary to mediate the synergistic effects of AhR and TLR ligands. Inhibitor studies and analysis of BMM derived from knockout mice confirmed that the synergistic induction of IL-22 by AhR and TLR ligands depend on the expression of AhR and Nuclear Factor-kappa B (NF-κB) member RelB. The exposure to particulate matter (PM) collected from traffic related air pollution (TRAP) and wildfires activated AhR as well as NF-κB signaling and significantly induced the expression of IL-22. In summary this study shows that simultaneous activation of the AhR and NF-κB signaling pathways leads to synergistic and prolonged induction of IL-22 by integrating signals of the canonical and non-canonical AhR pathway.

Dietary Tryptophan-Mediated Aryl Hydrocarbon Receptor Activation by the Gut Microbiota Alleviates Escherichia coli-Induced Endometritis in Mice

“…Alvarado et al found that enteropathogenic E. coli or inflammatory stimuli, such as dextran sodium sulfate, activated AhR via indoleamine 2,3-dioxygenase 1 (IDO1), which increased the resistance to enteropathogenic E. coli infection and colitis ( 30 ). Another study indicated that macrophages expressed and produced interleukin (IL)-22 after activation of AhR when cells were activated by the Toll-like receptor (TLR) family ( 31 ). The main virulence factor of E. coli , lipopolysaccharide (LPS), directly activated AhR, which in turn limits the LPS-induced inflammatory response in macrophages ( 32 ).…”

Polycyclic aromatic hydrocarbons in urban particle matter exacerbate movement disorder after ischemic stroke via potentiation of neuroinflammation

“…This PM2.5 contains many endotoxins compared with CRM28, and we previously reported that not only PAHs contained in urban PM2.5 but also endotoxins induce inflammatory reactions [ 35 ]. In addition, we suggested the crosstalk of AhR pathway and Toll-like receptor pathway [ 36 ]. Therefore, the deterioration of prognosis observed here may be due to endotoxins in addition to PAHs in urban PM2.5.…”

A Novel Aryl Hydrocarbon Receptor Antagonist HBU651 Ameliorates Peripheral and Hypothalamic Inflammation in High-Fat Diet-Induced Obese Mice

“…As AhR is highly expressed in a number of immune cells, AhR signaling plays important roles in the immune system in health and disease, and provides a molecular pathway to integrate the environment and metabolism in the immune responses [ 46 ]. In particular, ligand-activated AhR induces NF-κB-dependent transcription of inflammatory cytokines and chemokines [ 23 , 47 ], and may be linked with obesity and obesity-induced peripheral and central inflammation [ 48 ]. Various studies, including human cohort studies, support that inhibition of the AhR pathway or aberrant AhR activation may be a good therapeutic strategy for metabolic diseases.…”