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

Chao Hou; Dong Wang; Mingxia Zhao; Petek Ballar; Xinru Zhang; Qiong Mei; Wei Wang; Xiang Li; Qiang Sheng; Jun Liu; Chuansheng Wei; Yujun Shen; Yi Yang; Peng Wang; Juntang Shao; Sa Xu; Fuyan Wang; Yang Sun; Yuxian Shen

doi:10.1016/j.apsb.2023.07.027

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

Acta Pharm Sin B. 2023 Oct;13(10):4234-4252. doi: 10.1016/j.apsb.2023.07.027. Epub 2023 Aug 1.

Authors

Chao Hou^{1

2}, Dong Wang^{1

2}, Mingxia Zhao^{1

2}, Petek Ballar³, Xinru Zhang^{1

2}, Qiong Mei^{1

2}, Wei Wang^{1

2}, Xiang Li^{1

2}, Qiang Sheng^{1

2}, Jun Liu^{1

2}, Chuansheng Wei^{1

2}, Yujun Shen^{1

2}, Yi Yang^{1

2}, Peng Wang^{1

2}, Juntang Shao^{1

2}, Sa Xu^{1

2}, Fuyan Wang^{1

2}, Yang Sun⁴, Yuxian Shen^{1

2}

Affiliations

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.

Abstract

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 CCl₄-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.

Keywords: HSCs activation; Hepatic fibrosis; Ly6Chigh macrophages; Macrophage differentiation; Mesencephalic astrocyte-derived neurotrophic factor; NF-κB pathway; S100A8/S100A9; TLR4.