Silencing of aryl hydrocarbon receptor repressor restrains Th17 cell immunity in autoimmune hepatitis

Li Gao; Wei Zhang; Lina Zhang; Barbora Gromova; Guanqing Chen; Eva Csizmadia; Cortney Cagle; Silvia Nastasio; Yun Ma; Alan Bonder; Vilas Patwardhan; Simon C Robson; Sizun Jiang; Maria Serena Longhi

doi:10.1016/j.jaut.2023.103162

Silencing of aryl hydrocarbon receptor repressor restrains Th17 cell immunity in autoimmune hepatitis

J Autoimmun. 2024 Feb:143:103162. doi: 10.1016/j.jaut.2023.103162. Epub 2023 Dec 23.

Authors

Li Gao¹, Wei Zhang², Lina Zhang³, Barbora Gromova⁴, Guanqing Chen⁵, Eva Csizmadia⁶, Cortney Cagle⁷, Silvia Nastasio⁸, Yun Ma⁹, Alan Bonder¹⁰, Vilas Patwardhan¹¹, Simon C Robson¹², Sizun Jiang¹³, Maria Serena Longhi¹⁴

Affiliations

¹ Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Department of Endocrinology and Metabolism, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China. Electronic address: ligao001@hotmail.com.
² Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Department of Endocrinology and Metabolism, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China. Electronic address: doctorzhangwei001@163.com.
³ Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; School of Arts and Sciences, Tufts University, Medford, MA, USA. Electronic address: Linazhang2008@gmail.com.
⁴ Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia. Electronic address: b.gromova@gmail.com.
⁵ Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address: gchen7@bidmc.harvard.edu.
⁶ Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address: ecsizmad@bidmc.harvard.edu.
⁷ Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address: ccagle@bidmc.harvard.edu.
⁸ Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA. Electronic address: Silvia.Nastasio@childrens.harvard.edu.
⁹ Institute of Liver Studies, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK. Electronic address: yun.ma@kcl.ac.uk.
¹⁰ Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address: abonder@bidmc.harvard.edu.
¹¹ Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address: vpatward@bidmc.harvard.edu.
¹² Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address: srobson@bidmc.harvard.edu.
¹³ Center for Virology and Vaccine Research, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address: sjiang3@bidmc.harvard.edu.
¹⁴ Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address: mlonghi@bidmc.harvard.edu.

PMID: 38142533
PMCID: PMC10981568 (available on 2025-02-01)
DOI: 10.1016/j.jaut.2023.103162

Abstract

Th17-cells play a key role in the pathogenesis of autoimmune hepatitis (AIH). Dysregulation of Th17-cells in AIH is linked to defective response to aryl-hydrocarbon-receptor (AhR) activation. AhR modulates adaptive immunity and is regulated by aryl-hydrocarbon-receptor-repressor (AHRR), which inhibits AhR transcriptional activity. In this study, we investigated whether defective Th17-cell response to AhR derives from aberrant AHRR regulation in AIH. Th17-cells, obtained from the peripheral blood of AIH patients (n = 30) and healthy controls (n = 30) were exposed to AhR endogenous ligands, and their response assessed in the absence or presence of AHRR silencing. Therapeutic effects of AHRR blockade were tested in a model of Concanavalin-A (Con-A)-induced liver injury in humanized mice. AHRR was markedly upregulated in AIH Th17-cells, following exposure to l-kynurenine, an AhR endogenous ligand. In patients, silencing of AHRR boosted Th17-cell response to l-kynurenine, as reflected by increased levels of CYP1A1, the main gene controlled by AhR; and decreased IL17A expression. Blockade of AHRR limited the differentiation of naïve CD4-cells into Th17 lymphocytes; and modulated Th17-cell metabolic profile by increasing the levels of uridine via ATP depletion or pyrimidine salvage. Treatment with 2'-deoxy-2'-fluoro-d-arabinonucleic acid (FANA) oligonucleotides to silence human AHRR in vivo, reduced ALT levels, attenuated lymphocyte infiltration on histology, and heightened frequencies of regulatory immune subsets in NOD/scid/gamma mice, reconstituted with human CD4 cells, and exposed to Con-A. In conclusion, blockade of AHRR in AIH restores Th17-cell response to AHR, and limits Th17-cell differentiation through generation of uridine. In vivo, silencing of AHRR attenuates liver damage in NOD/scid/gamma mice. Blockade of AHRR might therefore represent a novel therapeutic strategy to modulate effector Th17-cell immunity and restore homeostasis in AIH.

Keywords: AHR; AHRR; AIH; Th17 cells.

MeSH terms

Animals
Hepatitis, Autoimmune* / genetics
Humans
Hydrocarbons
Kynurenine
Mice
Mice, Inbred NOD
Receptors, Aryl Hydrocarbon* / genetics
Receptors, Aryl Hydrocarbon* / metabolism
Repressor Proteins / genetics
Th17 Cells / metabolism
Uridine

Substances

Hydrocarbons
Kynurenine
Receptors, Aryl Hydrocarbon
Repressor Proteins
Uridine
AHR protein, human
Ahr protein, mouse

Abstract

MeSH terms

Substances

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