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ResearchIn-Press PreviewImmunology Open Access | 10.1172/JCI175305

The Nr4a family regulates intrahepatic Treg proliferation and liver fibrosis in MASLD models

Daisuke Aki,1 Taeko Hayakawa,1 Tanakorn Srirat,1 Shigeyuki Shichino,2 Minako Ito,3 Shin-Ichiroh Saitoh,4 Setsuko Mise-Omata,1 and Akihiko Yoshimura1

1Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan

2Division of Molecular Regulation of Inflammatory and Immune Diseases, Resea, Tokyo University of Science, Chiba, Japan

3Division of Allergy and Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Intractable Disorders, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

Find articles by Aki, D. in: JCI | PubMed | Google Scholar

1Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan

2Division of Molecular Regulation of Inflammatory and Immune Diseases, Resea, Tokyo University of Science, Chiba, Japan

3Division of Allergy and Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Intractable Disorders, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

Find articles by Hayakawa, T. in: JCI | PubMed | Google Scholar

1Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan

2Division of Molecular Regulation of Inflammatory and Immune Diseases, Resea, Tokyo University of Science, Chiba, Japan

3Division of Allergy and Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Intractable Disorders, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

Find articles by Srirat, T. in: JCI | PubMed | Google Scholar

1Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan

2Division of Molecular Regulation of Inflammatory and Immune Diseases, Resea, Tokyo University of Science, Chiba, Japan

3Division of Allergy and Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Intractable Disorders, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

Find articles by Shichino, S. in: JCI | PubMed | Google Scholar

1Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan

2Division of Molecular Regulation of Inflammatory and Immune Diseases, Resea, Tokyo University of Science, Chiba, Japan

3Division of Allergy and Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Intractable Disorders, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

Find articles by Ito, M. in: JCI | PubMed | Google Scholar

1Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan

2Division of Molecular Regulation of Inflammatory and Immune Diseases, Resea, Tokyo University of Science, Chiba, Japan

3Division of Allergy and Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Intractable Disorders, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

Find articles by Saitoh, S. in: JCI | PubMed | Google Scholar

1Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan

2Division of Molecular Regulation of Inflammatory and Immune Diseases, Resea, Tokyo University of Science, Chiba, Japan

3Division of Allergy and Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Intractable Disorders, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

Find articles by Mise-Omata, S. in: JCI | PubMed | Google Scholar

1Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan

2Division of Molecular Regulation of Inflammatory and Immune Diseases, Resea, Tokyo University of Science, Chiba, Japan

3Division of Allergy and Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

4Department of Intractable Disorders, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

Find articles by Yoshimura, A. in: JCI | PubMed | Google Scholar

Published October 15, 2024 - More info

J Clin Invest. https://doi.org/10.1172/JCI175305.
Copyright © 2024, Aki et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 15, 2024 - Version history
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Abstract

Nonalcoholic steatohepatitis (NASH) is a chronic progressive liver disease and highly prevalent worldwide. NASH is characterized by hepatic steatosis, inflammation, fibrosis and liver damage, which eventually results in liver dysfunction due to cirrhosis or hepatocellular carcinoma. However, the cellular and molecular mechanisms underlying NASH progression remain largely unknown. Here, we found an increase of Nr4a family of orphan nuclear receptors expression in intrahepatic T cells from mice with diet-induced NASH. Loss of Nr4a1 and Nr4a2 in T cell (dKO) ameliorated liver cell death and fibrosis, thereby mitigating liver dysfunction in NASH mice. dKO resulted in reduction of infiltrated macrophages and Th1/Th17 cells, whereas massive accumulation of T regulatory (Treg) cells in the liver of NASH mice. Combined single-cell RNA transcriptomic and TCR sequencing analysis revealed that intrahepatic dKO Tregs exhibited enhanced TIGIT and IL10 expression and were clonally expanded during NASH progression. Mechanistically, we found that dKO Tregs expressed high levels of Batf which promotes Treg cell proliferation and function upon TCR stimulation. Collectively, our findings not only provide an insight into the impact of intrahepatic Treg cells on NASH pathogenesis, but also suggest a therapeutic potential of targeting of Nr4a family to treat the disease.

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