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

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 Ly6Chigh macrophages and promoted HSCs activation. Furthermore, MANFsufficient 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-KB 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 -KB pathway, which exerts an impact on macrophage differentiation and shed light on hepatic fibrosis treatment.

Automated summary

This study reveals that the neurotrophic factor, mesencephalic astrocyte-derived neurotrophic factor (MANF), is upregulated in fibrotic liver tissues and plays a role in hepatic fibrosis. MANF deficiency worsens hepatic fibrosis, while transfusion of MANF-sufficient macrophages ameliorates fibrosis. Mechanistically, MANF interacts with S100A8 to inhibit TLR4-NF-KB signaling activation. Additionally, recombinant human MANF administration reduces hepatic fibrosis. This study provides insight into the treatment of hepatic fibrosis.