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Article: Macrophage p38α promotes nutritional steatohepatitis through M1 polarization

TitleMacrophage p38α promotes nutritional steatohepatitis through M1 polarization
Authors
Keywordsp38 MAPK
Hepatocytes
Macrophages
Steatohepatitis
Pro-inflammatory cytokines
Issue Date2019
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep
Citation
Journal of Hepatology, 2019, v. 71 n. 1, p. 163-174 How to Cite?
AbstractBackground & Aims: p38 mitogen-activated protein kinases are important inflammatory factors. p38α alteration has been implicated in both human and mouse inflammatory disease models. Therefore, we aimed to characterize the cell type-specific role of p38α in non-alcoholic steatohepatitis (NASH). Methods: Human liver tissues were obtained from 27 patients with non-alcoholic fatty liver disease (NAFLD) and 20 control individuals. NASH was established and compared between hepatocyte-specific p38α knockout (p38αΔHep), macrophage-specific p38α knockout (p38αΔMΦ) and wild-type (p38αfl/fl) mice fed with high-fat diet (HFD), high-fat/high-cholesterol diet (HFHC), or methionine-and choline-deficient diet (MCD). p38 inhibitors were administered to HFHC-fed wild-type mice for disease treatment. Results: p38α was significantly upregulated in the liver tissues of patients with NAFLD. Compared to p38αfl/fl littermates, p38αΔHep mice developed significant nutritional steatohepatitis induced by HFD, HFHC or MCD. Meanwhile, p38αΔMΦ mice exhibited less severe steatohepatitis and insulin resistance than p38αfl/fl mice in response to a HFHC or MCD. The effect of macrophage p38α in promoting steatohepatitis was mediated by the induction of pro-inflammatory factors (CXCL2, IL-1β, CXCL10 and IL-6) secreted by M1 macrophages and associated signaling pathways. p38αΔMΦ mice exhibited M2 anti-inflammatory polarization as demonstrated by increased CD45+F4/80+CD11b+CD206+ M2 macrophages and enhanced arginase activity in liver tissues. Primary hepatocytes from p38αΔMΦ mice showed decreased steatosis and inflammatory damage. In a co-culture system, p38α deleted macrophages attenuated steatohepatitic changes in hepatocytes through decreased secretion of pro-inflammatory cytokines (TNF-α, CXCL10 and IL-6), which mediate M1 macrophage polarization in p38αΔMΦ mice. Restoration of TNF-α, CXCL10 or IL‐6 induced lipid accumulation and inflammatory responses in p38αfl/fl hepatocytes co-cultured with p38αΔMΦ macrophages. Moreover, pharmacological p38 inhibitors suppressed HFHC-induced steatohepatitis. Conclusions: Macrophage p38α promotes the progression of steatohepatitis by inducing pro-inflammatory cytokine secretion and M1 polarization. p38 inhibition protects against steatohepatitis.
Descriptioneid_2-s2.0-85065031135
Persistent Identifierhttp://hdl.handle.net/10722/272993
ISSN
2017 Impact Factor: 15.04
2015 SCImago Journal Rankings: 4.570

 

DC FieldValueLanguage
dc.contributor.authorZhang, X-
dc.contributor.authorFan, L-
dc.contributor.authorWu, J-
dc.contributor.authorXu, H-
dc.contributor.authorLeung, WY-
dc.contributor.authorFu, K-
dc.contributor.authorWu, J-
dc.contributor.authorLiu, K-
dc.contributor.authorMan, K-
dc.contributor.authorYang, X-
dc.contributor.authorHan, J-
dc.contributor.authorRen, J-
dc.contributor.authorYu, J-
dc.date.accessioned2019-08-06T09:20:34Z-
dc.date.available2019-08-06T09:20:34Z-
dc.date.issued2019-
dc.identifier.citationJournal of Hepatology, 2019, v. 71 n. 1, p. 163-174-
dc.identifier.issn0168-8278-
dc.identifier.urihttp://hdl.handle.net/10722/272993-
dc.descriptioneid_2-s2.0-85065031135-
dc.description.abstractBackground & Aims: p38 mitogen-activated protein kinases are important inflammatory factors. p38α alteration has been implicated in both human and mouse inflammatory disease models. Therefore, we aimed to characterize the cell type-specific role of p38α in non-alcoholic steatohepatitis (NASH). Methods: Human liver tissues were obtained from 27 patients with non-alcoholic fatty liver disease (NAFLD) and 20 control individuals. NASH was established and compared between hepatocyte-specific p38α knockout (p38αΔHep), macrophage-specific p38α knockout (p38αΔMΦ) and wild-type (p38αfl/fl) mice fed with high-fat diet (HFD), high-fat/high-cholesterol diet (HFHC), or methionine-and choline-deficient diet (MCD). p38 inhibitors were administered to HFHC-fed wild-type mice for disease treatment. Results: p38α was significantly upregulated in the liver tissues of patients with NAFLD. Compared to p38αfl/fl littermates, p38αΔHep mice developed significant nutritional steatohepatitis induced by HFD, HFHC or MCD. Meanwhile, p38αΔMΦ mice exhibited less severe steatohepatitis and insulin resistance than p38αfl/fl mice in response to a HFHC or MCD. The effect of macrophage p38α in promoting steatohepatitis was mediated by the induction of pro-inflammatory factors (CXCL2, IL-1β, CXCL10 and IL-6) secreted by M1 macrophages and associated signaling pathways. p38αΔMΦ mice exhibited M2 anti-inflammatory polarization as demonstrated by increased CD45+F4/80+CD11b+CD206+ M2 macrophages and enhanced arginase activity in liver tissues. Primary hepatocytes from p38αΔMΦ mice showed decreased steatosis and inflammatory damage. In a co-culture system, p38α deleted macrophages attenuated steatohepatitic changes in hepatocytes through decreased secretion of pro-inflammatory cytokines (TNF-α, CXCL10 and IL-6), which mediate M1 macrophage polarization in p38αΔMΦ mice. Restoration of TNF-α, CXCL10 or IL‐6 induced lipid accumulation and inflammatory responses in p38αfl/fl hepatocytes co-cultured with p38αΔMΦ macrophages. Moreover, pharmacological p38 inhibitors suppressed HFHC-induced steatohepatitis. Conclusions: Macrophage p38α promotes the progression of steatohepatitis by inducing pro-inflammatory cytokine secretion and M1 polarization. p38 inhibition protects against steatohepatitis.-
dc.languageeng-
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep-
dc.relation.ispartofJournal of Hepatology-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectp38 MAPK-
dc.subjectHepatocytes-
dc.subjectMacrophages-
dc.subjectSteatohepatitis-
dc.subjectPro-inflammatory cytokines-
dc.titleMacrophage p38α promotes nutritional steatohepatitis through M1 polarization-
dc.typeArticle-
dc.identifier.emailMan, K: kwanman@hku.hk-
dc.identifier.authorityMan, K=rp00417-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.jhep.2019.03.014-
dc.identifier.pmid30914267-
dc.identifier.scopuseid_2-s2.0-85065031135-
dc.identifier.hkuros300410-
dc.identifier.volume71-
dc.identifier.issue1-
dc.identifier.spage163-
dc.identifier.epage174-
dc.publisher.placeNetherlands-

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