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

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dc.authorscopusid57201614628
dc.authorscopusid58362810900
dc.authorscopusid58542125600
dc.authorscopusid6504012138
dc.authorscopusid57799768400
dc.authorscopusid57217424508
dc.authorscopusid58542452300
dc.contributor.authorHou, C.
dc.contributor.authorWang, D.
dc.contributor.authorZhao, M.
dc.contributor.authorBallar, P.
dc.contributor.authorZhang, X.
dc.contributor.authorMei, Q.
dc.contributor.authorWang, W.
dc.date.accessioned2024-08-25T18:51:05Z
dc.date.available2024-08-25T18:51:05Z
dc.date.issued2023
dc.departmentEge Üniversitesien_US
dc.description.abstractThe 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-?B 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-?B pathway, which exerts an impact on macrophage differentiation and shed light on hepatic fibrosis treatment. © 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciencesen_US
dc.description.sponsorshipNational Natural Science Foundation of China, NSFC: 81973336, U21A20345en_US
dc.description.sponsorshipWe would like to thank Prof. Jia Luo from the University of Kentucky for supplying MANF conditional knockout mice. This work was supported by the National Natural Science Foundation of China ( 81973336 ) and the Joint Fund of the National Natural Science Foundation of China ( U21A20345 ).en_US
dc.identifier.doi10.1016/j.apsb.2023.07.027
dc.identifier.issn2211-3835
dc.identifier.scopus2-s2.0-85168381683en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1016/j.apsb.2023.07.027
dc.identifier.urihttps://hdl.handle.net/11454/102465
dc.indekslendigikaynakScopusen_US
dc.language.isoenen_US
dc.publisherChinese Academy of Medical Sciencesen_US
dc.relation.ispartofActa Pharmaceutica Sinica Ben_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.snmz20240825_Gen_US
dc.subjectHepatic fibrosisen_US
dc.subjectHSCs activationen_US
dc.subjectLy6Chigh macrophagesen_US
dc.subjectMacrophage differentiationen_US
dc.subjectMesencephalic astrocyte-derived neurotrophic factoren_US
dc.subjectNF-?B pathwayen_US
dc.subjectS100A8/S100A9en_US
dc.subjectTLR4en_US
dc.titleMANF brakes TLR4 signaling by competitively binding S100A8 with S100A9 to regulate macrophage phenotypes in hepatic fibrosisen_US
dc.typeArticleen_US

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