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<p>Immune dysregulation-induced inflammation serves as a driving force in the progression of metabolic dysfunction-associated steatohepatitis (MASH), while the underlying cellular and molecular mechanisms remain largely uncharted. A Western diet (WD) is employed to construct mouse models of metabolic dysfunction associated steatotic liver disease (MASLD) or MASH. Mass cytometry identifies a c-kit<sup>+</sup> cDC1 subset whose frequency is reduced in the livers of mice and patients with MASH compared with healthy controls. Adoptive cell transfer of c-kit<sup>+</sup> cDC1 protects the progression of MASH. Moreover, analysis of gut microbe sequence shows that WD-fed mice and MASLD/MASH patients exhibit gut microbiota dysbiosis, with an elevated abundance of H<sub>2</sub>S-producing <i>Desulfovibrio_sp</i>. Transplanting of MASH-derived fecal flora, <i>Desulfovibrio_sp</i>., or injecting H<sub>2</sub>S intraperitoneally into MASLD mice decreases the c-kit<sup>+</sup>cDC1 population and exacerbates liver inflammation. Mechanistically, H<sub>2</sub>S induces autophagic cell death of cDC1 in a c-kit-dependent manner in cDC-specific c-kit<sup>-/-</sup> and Atg5<sup>-/-</sup> mice. We thus uncover that microbiota-derived H<sub>2</sub>S triggers the autophagic cell death of c-kit<sup>+</sup> cDC1 and ignites the liver inflammatory cascade in MASH.</p>

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Microbiota-derived H2S induces c-kit+ cDC1 autophagic cell death and liver inflammation in metabolic dysfunction-associated steatohepatitis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月5日

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  • Yuxiang Song,
  • Na Li,
  • Shang Jiang,
  • Kexin Wang,
  • Guoyue Lv,
  • Zhongqi Fan,
  • Xiliang Du,
  • Wenwen Gao,
  • Lin Lei,
  • Zhe Wang,
  • Guowen Liu,
  • Xinwei Li

摘要

Immune dysregulation-induced inflammation serves as a driving force in the progression of metabolic dysfunction-associated steatohepatitis (MASH), while the underlying cellular and molecular mechanisms remain largely uncharted. A Western diet (WD) is employed to construct mouse models of metabolic dysfunction associated steatotic liver disease (MASLD) or MASH. Mass cytometry identifies a c-kit+ cDC1 subset whose frequency is reduced in the livers of mice and patients with MASH compared with healthy controls. Adoptive cell transfer of c-kit+ cDC1 protects the progression of MASH. Moreover, analysis of gut microbe sequence shows that WD-fed mice and MASLD/MASH patients exhibit gut microbiota dysbiosis, with an elevated abundance of H2S-producing Desulfovibrio_sp. Transplanting of MASH-derived fecal flora, Desulfovibrio_sp., or injecting H2S intraperitoneally into MASLD mice decreases the c-kit+cDC1 population and exacerbates liver inflammation. Mechanistically, H2S induces autophagic cell death of cDC1 in a c-kit-dependent manner in cDC-specific c-kit-/- and Atg5-/- mice. We thus uncover that microbiota-derived H2S triggers the autophagic cell death of c-kit+ cDC1 and ignites the liver inflammatory cascade in MASH.