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Updated: Jul 14, 2025
Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
Published on: January 7, 2019
MANF brakes TLR4 signaling by competitively binding S100A8 with S100A9 to regulate macrophage phenotypes in hepatic
Chao Hou1,2, Dong Wang1,2, Mingxia Zhao1,2
1School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, 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 Ly6Chigh 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.
Insights
Mesencephalic astrocyte-derived neurotrophic factor (MANF) exacerbates hepatic fibrosis when deficient, particularly in macrophages. MANF administration alleviates liver fibrosis by inhibiting the S100A8/A9-TLR4-NF-κB pathway.
Area of Science:
- Hepatology
- Immunology
- Molecular Biology
Background:
- Hepatic fibrosis is a significant cause of chronic liver disease.
- The role of mesencephalic astrocyte-derived neurotrophic factor (MANF) in liver fibrosis remains unexplored.
Purpose of the Study:
- To investigate the role of MANF in hepatic fibrosis.
- To elucidate the underlying mechanism of MANF's action in liver fibrosis.
Main Methods:
- Analysis of MANF expression in human fibrotic liver tissues and CCl4-treated mice.
- Generation of hepatocyte-specific and myeloid-specific MANF knockout mouse models.
- Macrophage transfusion experiments and pharmacological administration of recombinant human MANF.
- Investigation of molecular interactions involving MANF, S100A8, S100A9, TLR4, and NF-κB signaling.
Main Results:
- MANF was upregulated in fibrotic liver tissues.
- MANF deficiency, especially in hepatic macrophages, exacerbated fibrosis by increasing Ly6Chigh macrophages and promoting HSC activation.
- MANF transfusion ameliorated fibrosis in MANF-deficient mice.
- MANF directly interacted with S100A8, inhibiting S100A8/A9 heterodimer formation and TLR4-NF-κB activation.
- Systemic MANF administration significantly alleviated CCl4-induced hepatic fibrosis.
Conclusions:
- MANF plays a protective role against hepatic fibrosis, primarily through its action in hepatic macrophages.
- MANF acts as a negative regulator of the S100A8/A9-TLR4-NF-κB pathway, impacting macrophage differentiation and HSC activation.
- MANF represents a potential therapeutic target for treating liver fibrosis.
