The Nr4a family regulates intrahepatic Treg proliferation and liver fibrosis in MASLD models
Daisuke Aki, … , Setsuko Mise-Omata, Akihiko Yoshimura
Daisuke Aki, … , Setsuko Mise-Omata, Akihiko Yoshimura
Published October 15, 2024
Citation Information: J Clin Invest. 2024;134(23):e175305. https://doi.org/10.1172/JCI175305.
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Research Article Immunology

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

Abstract

Metabolic dysfunction–associated steatotic hepatitis (MASH) is a chronic progressive liver disease that is highly prevalent worldwide. MASH is characterized by hepatic steatosis, inflammation, fibrosis, and liver damage, which eventually result in liver dysfunction due to cirrhosis or hepatocellular carcinoma. However, the cellular and molecular mechanisms underlying MASH progression remain largely unknown. Here, we found an increase of the Nr4a family of orphan nuclear receptor expression in intrahepatic T cells from mice with diet-induced MASH. Loss of Nr4a1 and Nr4a2 in T cell (dKO) ameliorated liver cell death and fibrosis, thereby mitigating liver dysfunction in MASH mice. dKO resulted in reduction of infiltrated macrophages and Th1/Th17 cells, whereas it led to a massive accumulation of Tregs in the liver of MASH mice. Combined single-cell RNA transcriptomic and TCR sequencing analysis revealed that intrahepatic dKO Tregs exhibited enhanced T cell immunoreceptor with Ig and ITIM domains (TIGIT) and IL-10 expression and were clonally expanded during MASH progression. Mechanistically, we found that dKO Tregs expressed high levels of basic leucine zipper ATF-like transcription factor (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 MASH pathogenesis, but also suggest a therapeutic potential of targeting of the Nr4a family to treat the disease.

Authors

Daisuke Aki, Taeko Hayakawa, Tanakorn Srirat, Shigeyuki Shichino, Minako Ito, Shin-Ichiroh Saitoh, Setsuko Mise-Omata, Akihiko Yoshimura

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Figure 1

MASH upregulates Nr4a family expression in hepatic T cells.

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MASH upregulates Nr4a family expression in hepatic T cells. (A and B) Ma...
(A and B) Male C57BL/6 mice were fed SD or CD for 12 weeks (n = 5 per group). mRNA expression of Nr4a1, Nr4a2, and Nr4a3 in hepatic CD4+ T cells (A) or hepatic CD8+ T cells (B). (C) mRNA expression of Nr4a1, Nr4a2, and Nr4a3 in stimulated CD4+ T cells. Splenic naive CD4+ T cells were stimulated with α-CD3 and α-CD28 antibodies in normal RPMI (normal), or methionine and choline-deficient (MCD) medium for the indicated times (n = 4 per group). (D) Splenic naive CD4+ T cells from Nr4a3-EGFP reporter mice were stimulated with α-CD3 and α-CD28 antibodies in normal RPMI or MCD medium for 3 days, and GFP expression was assessed by flow cytometry. Representative flow cytometry plots (left) and percentages (right) of GFPhi cells (n = 6 per group). Primers used for quantitative PCR are listed in Supplemental Table 1. Data are represented as means ± SEM. P values were calculated using unpaired 2-tailed Student’s t test or Mann-Whitney U test (A–D). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.