Altered aryl-hydrocarbon-receptor signalling affects regulatory and effector cell immunity in autoimmune hepatitis

TY - JOUR

T1 - Altered aryl-hydrocarbon-receptor signalling affects regulatory and effector cell immunity in autoimmune hepatitis

AU - Vuerich, Marta

AU - Harshe, Rasika

AU - Frank, Luiza Abrahão

AU - Mukherjee, Samiran

AU - Gromova, Barbora

AU - Csizmadia, Eva

AU - Nasser, Imad A.M.

AU - Ma, Yun

AU - Bonder, Alan

AU - Patwardhan, Vilas

AU - Robson, Simon C.

AU - Longhi, Maria Serena

N1 - Funding Information: This work has been supported by the National Institutes of Health ( R01 DK108894 to M.S.L. and R21 CA164970 to S.C.R.); AASLD Pilot Research Award (to M.S.L.); Seed Grant Award (Department of Anesthesia, Critical Care and Pain Medicine to M.S.L.); Department of Defense Award W81XWH-16-0464 (to S.C.R.); Postdoctoral Fellowship from CAPES , Brazil ( 88881.171857/2018-01 to L.A.F.); and Scholarship Dr. Ludmily Sedlarovey-Rabanovej and Nadacia Tatra banky (to B.G.). Publisher Copyright: © 2020 European Association for the Study of the Liver Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/1

Y1 - 2021/1

N2 - Background & Aims: In autoimmune hepatitis (AIH), the imbalance between regulatory T cells (Tregs) and T-helper type 17 (Th17) cells has been linked to low levels of CD39, an ectoenzyme that hydrolyses ATP, ultimately generating immunosuppressive adenosine. Upregulation of CD39 results from activation of aryl hydrocarbon receptor (AHR), which mediates toxin responses to modulate T-cell immunity. In this study, we investigated whether altered AHR signalling underlies defective CD39 expression and function in AIH Tregs and Th17 cells, therefore contributing to regulatory/effector cell imbalance. Methods: Tregs and Th17 cells, obtained from the peripheral blood of 49 patients with AIH and 21 healthy individuals (HI), were tested for response to endogenous and exogenous AHR ligands. Results: When compared to those of HI, AIH-derived Tregs and Th17 cells displayed impaired responses to AHR activation, reflected by impaired upregulation of CD39, delayed increase in ectoenzymatic activity, and defective Treg suppressive function. These impairments resulted, at least in part, from heightened levels of AHRR and Erα in Tregs and high HIF-1α in Th17 cells, and were reverted upon molecular blockade. Importantly, in AIH-derived Tregs, the binding affinity of AHR was higher for Erα than ARNT. Conclusions: In AIH, high levels of AHRR and HIF-1α inhibit AHR signalling in Tregs and Th17 cells. AHR non-canonical binding to Erα further amplifies the lack of effective CD39 upregulation. Blockade of these inhibitory and/or non-canonical activation pathways represents a potential therapeutic approach to restore CD39 and immunohomeostasis in AIH. Lay summary: In patients with autoimmune hepatitis, the imbalance between regulatory T cells and T helper type-17 cells is linked to dysfunction of the aryl hydrocarbon receptor pathway, resulting from aberrant inhibition or non-canonical activation. These alterations impair Treg- and Th17 cell-induced upregulation of CD39, an ectoenzyme key to immunoregulation. Blockade of excessive inhibition or non-canonical activation of the aryl hydrocarbon receptor pathway might represent a novel therapeutic strategy to control inflammation while restoring immune balance in autoimmune hepatitis.

AB - Background & Aims: In autoimmune hepatitis (AIH), the imbalance between regulatory T cells (Tregs) and T-helper type 17 (Th17) cells has been linked to low levels of CD39, an ectoenzyme that hydrolyses ATP, ultimately generating immunosuppressive adenosine. Upregulation of CD39 results from activation of aryl hydrocarbon receptor (AHR), which mediates toxin responses to modulate T-cell immunity. In this study, we investigated whether altered AHR signalling underlies defective CD39 expression and function in AIH Tregs and Th17 cells, therefore contributing to regulatory/effector cell imbalance. Methods: Tregs and Th17 cells, obtained from the peripheral blood of 49 patients with AIH and 21 healthy individuals (HI), were tested for response to endogenous and exogenous AHR ligands. Results: When compared to those of HI, AIH-derived Tregs and Th17 cells displayed impaired responses to AHR activation, reflected by impaired upregulation of CD39, delayed increase in ectoenzymatic activity, and defective Treg suppressive function. These impairments resulted, at least in part, from heightened levels of AHRR and Erα in Tregs and high HIF-1α in Th17 cells, and were reverted upon molecular blockade. Importantly, in AIH-derived Tregs, the binding affinity of AHR was higher for Erα than ARNT. Conclusions: In AIH, high levels of AHRR and HIF-1α inhibit AHR signalling in Tregs and Th17 cells. AHR non-canonical binding to Erα further amplifies the lack of effective CD39 upregulation. Blockade of these inhibitory and/or non-canonical activation pathways represents a potential therapeutic approach to restore CD39 and immunohomeostasis in AIH. Lay summary: In patients with autoimmune hepatitis, the imbalance between regulatory T cells and T helper type-17 cells is linked to dysfunction of the aryl hydrocarbon receptor pathway, resulting from aberrant inhibition or non-canonical activation. These alterations impair Treg- and Th17 cell-induced upregulation of CD39, an ectoenzyme key to immunoregulation. Blockade of excessive inhibition or non-canonical activation of the aryl hydrocarbon receptor pathway might represent a novel therapeutic strategy to control inflammation while restoring immune balance in autoimmune hepatitis.

KW - AHR

KW - AIH

KW - Ectoenzyme

KW - HIF-1α

UR - http://www.scopus.com/inward/record.url?scp=85091682655&partnerID=8YFLogxK

U2 - 10.1016/j.jhep.2020.06.044

DO - 10.1016/j.jhep.2020.06.044

M3 - Article

C2 - 32663496

AN - SCOPUS:85091682655

SN - 0168-8278

VL - 74

SP - 48

EP - 57

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 1

ER -