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

Yasuhiro Ishihara,Sarah Y Kado,Christoph F A Vogel,Yi He,Keith J Bein,Arshia A Pouraryan,Colleen Sweeney,Angelika Urban,Thomas Haarmann-Stemmann

doi:10.3389/ftox.2021.787360

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.

Highlights

The aryl hydrocarbon receptor (AhR) plays an important role in regulating immune responses (Stockinger et al, 2014; Gutiérrez-Vázquez and Quintana, 2018)
We reported that TCDD as well as polycyclic aromatic hydrocarbons (PAHs)-containing particulate matter (PM) directly activate AhR and induce inflammatory markers associated with an enhanced activation of dendritic cells (DC) responsible for differentiation of naive T cells towards a T helper 17 (Th17)-like phenotype and an increased production of interleukin 22 (IL-22) (Castañeda et al, 2018)
In contrast to LPS alone, the addition of the AhR ligand TCDD significantly increased the expression of IL-22 in LPSactivated bone marrow-derived macrophages (BMM) and led to a sustained elevated level of 290-fold at 48 h

Summary

Introduction

The aryl hydrocarbon receptor (AhR) plays an important role in regulating immune responses (Stockinger et al, 2014; Gutiérrez-Vázquez and Quintana, 2018). We reported that TCDD as well as PAH-containing PM directly activate AhR and induce inflammatory markers associated with an enhanced activation of DC responsible for differentiation of naive T cells towards a Th17-like phenotype and an increased production of interleukin 22 (IL-22) (Castañeda et al, 2018). It became evident that AhR is a key player driving the production of IL-22 in innate lymphoid cells 3 (ILC3) and regulates the development of ILC3 controlling intestinal immunity and inflammation (Lee et al, 2011; Qiu et al, 2012). The expression of IL-22 triggered by IL-21 and IL-23 in Th17 cells was controlled by AhR and RAR-related orphan receptor gamma t (RORγt) (Kiss et al, 2011; Yeste et al, 2014)

Methods

Results

Conclusion