REVIEW © The Author(s) 2013. Published by Oxford University Press on behalf of The Japanese Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com The roles of aryl hydrocarbon receptor in immune responses Nam Trung Nguyen*, Hamza Hanieh*, Taisuke Nakahama* and Tadamitsu Kishimoto Laboratory of Immune Regulation, WPI-Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan Correspondence to: T. Kishimoto; E-mail: kishimoto@ifrec.osaka-u.ac.jp *These authors contributed equally to this article. Received 4 July 2012, accepted 27 February 2013 Abstract A number of recent studies have examined the functions of aryl hydrocarbon receptor (Ahr) in the immune system. Also known as dioxin receptor, Ahr is a ligand-activated transcription factor that serves as a receptor for various environmental toxins. The functions of Ahr in T cells depend on the specifc ligand bound to the receptor. For instance, binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin to Ahr suppresses experimental autoimmune encephalomyelitis (EAE) by promoting the development of Foxp3 + T reg cells, whereas 6-formylindolo[3,2-b]carbazole enhances EAE by inducing the differentiation of IL-17-producing T cells. Furthermore, specifcally deleting Ahr in T cells inhibits collagen-induced arthritis in mice. In macrophages and dendritic cells (DCs), Ahr is anti-infammatory. In response to LPS, Ahr-defcient macrophages show increased production of pro-infammatory cytokines, such as IL-6 and TNF-α, and Ahr-defcient DCs produce less of the anti-infammatory cytokine IL-10. In this review, we discuss the roles of Ahr in macrophages and T cells. Moreover, studies examining Ahr activation in other cell types have revealed additional contributions to B cell and osteoblast/osteoclast differentiation. We also briefy summarize the current understanding of regulatory mechanisms underlying Ahr activation in various cells and discuss the potential clinical implications of cell-specifc targeting of Ahr in pathologic conditions of the immune system. Keywords: dioxin receptor, immune regulation Introduction Aryl hydrocarbon receptor (Ahr) is a ligand-activated tran- scription factor that mediates numerous cellular responses to toxins and plays critical modulatory roles in various immune cells during innate and adaptive immune responses. Ahr was originally investigated as a receptor for environmental contaminants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). More recently, studies have examined Ahr in immune cells including T cells and antigen-presenting cells including dendritic cells (DCs) and macrophages. The balance between T h 17 cells and the other T-cell subsets is particularly critical to ensure that a specifc T-cell subset does not predominate and—together with other transcriptional changes—cause dis- orders associated with aberrant cytokine production. One approach has been to specifcally delete Ahr in mac- rophages or T cells. Mice lacking Ahr in macrophages or T cells are used as models of infammatory and autoimmune diseases, including LPS-induced shock and collagen-induced arthritis (CIA). In addition, Ahr has been investigated in experi- mental autoimmune encephalomyelitis (EAE) and dextran sulfate sodium (DSS)-induced colitis, among other disease models. In this review, we discuss the roles of Ahr in immune and non-immune cells, including contributions to various ani- mal models of disease. Importantly, the signaling cascades and biochemical processes associated with Ahr are promising avenues to modulate immune responses in the clinic. Ahr signaling pathways Ahr is a ligand-activated member of the Per-Arnt-Sim family of basic helix–loop–helix transcription factors. Normally, Ahr forms cytoplasmic complexes with various proteins, such as heat shock protein 90, Ahr-interacting protein and p23 (1–3). Binding of Ahr to a xenobiotic ligand, such as TCDD, induces translocation of the Ahr complex into the nucleus, where it binds Ahr nuclear translocator (Arnt). In the nucleus, Ahr–Arnt heterodimers bind xenobiotic-responsive elements (XREs) in the promoters of responsive genes, including those encoding members of the cytochrome P450 family (4–7). Ahr repressor—a marker of Ahr activation—attenuates Ahr signaling (8). International Immunology, Vol. 25, No. 6, pp. 335–343 doi:10.1093/intimm/dxt011 Advance Access publication 11 April 2013 Downloaded from https://academic.oup.com/intimm/article/25/6/335/733829 by guest on 31 July 2022