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MANF brakes TLR4 signaling by competitively binding S100A8 with S100A9 to regulate macrophage phenotypes in hepatic fibrosis

查看全文 作　　者：Chao [1,2]Hou;Dong [1,2]Wang;Mingxia [1,2]Zhao;Petek [3]Ballar;Xinru [1,2]Zhang;Qiong [1,2]Mei;Wei [1,2]Wang;Xiang [1,2]Li;Qiang [1,2]Sheng;Jun [1,2]Liu;Chuansheng [1,2]Wei;Yujun [1,2]Shen;Yi [1,2]Yang;Peng [1,2]Wang;Juntang [1,2]Shao;Sa [1,2]Xu;Fuyan [1,2]Wang;Yang [4]Sun;Yuxian [1,2]Shen 高影响力作者 机构地区：[1]School of Basic Medical Sciences,Anhui Medical University,Hefei 230032,China;[2]Biopharmaceutical Research Institute,Anhui Medical University,Hefei 230032,China;[3]Department of Biochemistry,Faculty of Pharmacy,Ege University,Izmir 35100,Turkey;[4]State Key Laboratory of Pharmaceutical Biotechnology,School of Life Sciences,Nanjing University,Nanjing 210023,China高影响力机构 出　　处：《Acta Pharmaceutica Sinica B》索引2023年第13卷第10期,共19页高影响力期刊 基　　金：supported by the National Natural Science Foundation of China(81973336);the Joint Fund of the National Natural Science Foundation of China(U21A20345)。 摘　　要：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 CCl4.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^(high)macrophages and promoted HSCs activation.Furthermore,MANF-sufficient macrophages(from WT mice)transfusion ameliorated CCl4-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-κB signal activation.Pharmacologically,systemic administration of recombinant human MANF significantly alleviated CCl_(4)-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-κB pathway,which exerts an impact on macrophage differentiation and shed light on hepatic fibrosis treatment. 关 键 词：Hepatic fibrosis Mesencephalic astrocyte-derived neurotrophic factor Macrophage differentiation Ly6C^(high)macrophages S100A8/S100A9 TLR4 NF-κB pathway HSCs activation
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