Hou Chao, Wang Dong, Zhao Mingxia, Ballar Petek, Zhang Xinru, Mei Qiong, Wang Wei, Li Xiang, Sheng Qiang, Liu Jun, Wei Chuansheng, Shen Yujun, Yang Yi, Wang Peng, Shao Juntang, Xu Sa, Wang Fuyan, Sun Yang, Shen Yuxian
School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China.
Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China.
Acta Pharm Sin B. 2023 Oct;13(10):4234-4252. doi: 10.1016/j.apsb.2023.07.027. Epub 2023 Aug 1.
The mesencephalic astrocyte-derived neurotrophic factor (MANF) has been recently identified as a neurotrophic factor, but its role in hepatic fibrosis is unknown. Here, we found that MANF was upregulated in the fibrotic liver tissues of the patients with chronic liver diseases and of mice treated with CCl. MANF deficiency in either hepatocytes or hepatic mono-macrophages, particularly in hepatic mono-macrophages, clearly exacerbated hepatic fibrosis. Myeloid-specific MANF knockout increased the population of hepatic Ly6C macrophages and promoted HSCs activation. Furthermore, MANF-sufficient macrophages (from WT mice) transfusion ameliorated CCl-induced hepatic fibrosis in myeloid cells-specific MANF knockout (MKO) mice. Mechanistically, MANF interacted with S100A8 to competitively block S100A8/A9 heterodimer formation and inhibited S100A8/A9-mediated TLR4-NF-B signal activation. Pharmacologically, systemic administration of recombinant human MANF significantly alleviated CCl-induced hepatic fibrosis in both WT and hepatocytes-specific MANF knockout (HKO) mice. This study reveals a mechanism by which MANF targets S100A8/A9-TLR4 as a "brake" on the upstream of NF-B pathway, which exerts an impact on macrophage differentiation and shed light on hepatic fibrosis treatment.
中脑星形胶质细胞衍生的神经营养因子（MANF）最近被鉴定为一种神经营养因子，但其在肝纤维化中的作用尚不清楚。在此，我们发现MANF在慢性肝病患者和接受四氯化碳处理的小鼠的纤维化肝组织中上调。肝细胞或肝内单核巨噬细胞中MANF缺乏，特别是肝内单核巨噬细胞中MANF缺乏，明显加剧了肝纤维化。髓系特异性MANF基因敲除增加了肝Ly6C巨噬细胞的数量并促进了肝星状细胞（HSCs）的激活。此外，输入MANF充足的巨噬细胞（来自野生型小鼠）可改善髓系细胞特异性MANF基因敲除（MKO）小鼠中四氯化碳诱导的肝纤维化。机制上，MANF与S100A8相互作用，竞争性地阻断S100A8/A9异二聚体的形成，并抑制S100A8/A9介导的TLR4-NF-κB信号激活。在药理学上，全身给予重组人MANF可显著减轻野生型和肝细胞特异性MANF基因敲除（HKO）小鼠中四氯化碳诱导的肝纤维化。本研究揭示了一种机制，即MANF靶向S100A8/A9-TLR4作为NF-κB途径上游的“刹车”，对巨噬细胞分化产生影响，并为肝纤维化治疗提供了新的思路。
