The aryl hydrocarbon receptor in liver inflammation

Abstract

The aryl hydrocarbon receptor (AHR) is a ubiquitously expressed ligand-activated transcription factor with multifaceted physiological functions. In the immune system, AHR has been unequivocally identified as a key regulatory factor that can integrate environmental, dietary, or microbial signals into innate and adaptive immune responses. Correspondingly, AHR activity seems to be most important at barrier organs, such as the gut, skin, and lung. The liver is likewise prominently exposed to gut-derived dietary or microbial AHR ligands and, moreover, generates plenty of AHR ligands itself. Yet, surprisingly little is known about the role of AHR in the regulation of hepatic immune responses, which are normally biased towards tolerance, preventing harmful inflammation in response to innocuous stimuli. In this review, we summarize the current knowledge about the role of AHR in hepatic immune responses in the healthy liver as well as in inflammatory liver disease. Moreover, we discuss AHR as a potential therapeutic target in hepatic disorders, including autoimmune liver disease, liver fibrosis, and liver cancer.

Keywords: AHR ligands; Aryl hydrocarbon receptor; Hepatic immune response; Hepatic tolerance; Liver inflammation; Therapy.

Fig. 1

AHR signaling pathway. The inactive AHR is complexed with the chaperon HSP90, co-chaperon p23, AIP, and c-SRC in the cytoplasm. Ligand binding results in conformational changes of AHR, dissociation of the protein complex, and AHR translocation into the nucleus. In the nucleus, AHR forms a heterodimer with ARNT. AHR/ARNT binds to dioxin/xenobiotic responsive elements (DRE/XRE), inducing transcription of various target genes. Additionally, in complex with other transcription factors, AHR can interact with alternative binding sites. AHR activation is limited in a negative feedback loop by the AHR repressor AHRR inhibiting AHR/ARNT dimer formation and by the AHR-induced enzymes CYP1A1 and CYP1A2 which degrade AHR ligands. Besides its transcriptional activity, AHR also functions as part of the E3 ubiquitin ligase complex driving the proteasomal degradation of target proteins, most notably of hormone receptors

Fig. 2

Functional role of AHR in liver disease. AHR activation can promote or dampen liver disease pathogenesis, as indicated by red or green arrows, respectively. AHR activating ligands can derive from various endogenous or exogenous sources or can be produced in the liver itself (see Table 1). (A) Acute phase response: AHR activation impairs NF-κB-mediated expression of acute phase genes such as Saa1/2 [47]. (B) Immune-mediated liver disease: anti-inflammatory CD39 expression on Treg or Th17 cells is AHR dependent [41]. AHR-mediated induction of suppressive MDSCs [38]. AHR controls protective IL-22 expression in ILCs and CD4+ T cells [34, 35, 37]. (C) APAP-induced liver injury: AHR activation induces the APAP-metabolizing enzyme CYP1A2, resulting in increased hepatotoxicity [52]. (D) Alcohol-induced liver injury: AHR activation reduces EtOH-induced oxidative stress, inflammation, and hepatocyte apoptosis [49, 50]. (E) HCC: increased production of the AHR ligand kynurenine via TDO and IDO1 results in upregulation of PD-L1, impaired CD8 T cell responses, and tumor progression [–68]. (F) Fibrosis: AHR-dependent IL-17 and IL-22 production as well as AHR activation via IDO2/Kyn can promote liver fibrosis [56, 57], while ITE-induced AHR activation in HSCs dampens liver fibrosis [54]. (G) NASH: AHR-induced CD36 [58], FGF21[61], as well as the AHR downstream molecules Cyp1a1 and TNF-α [59] promote NASH. Vice versa, AHR-induced Socs3 [62] and AHR-dependent induction of a Treg versus Th17 predominance [61] attenuate NASH. (H) AHR restricts anti-infectious immunity in Trypanosoma cruzi infection by promoting Tregs and inhibiting Th1 responses and CD8 T cell memory development [46]