Macrophage p38α promotes nutritional steatohepatitis through M1 polarization

Background & Aims: p38 mitogen-activated protein kinases are important inflammatory factors. p38 alpha alteration has been implicated in both human and mouse inflammatory disease models. Therefore, we aimed to characterize the cell type-specific role of p38 alpha 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 p38 alpha knockout (p38 alpha(Delta Hep)), macrophage-specific p38 alpha knockout (p38 alpha(Delta M Phi)) and wild-type (p38 alpha(fl/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: p38 alpha was significantly upregulated in the liver tissues of patients with NAFLD. Compared to p38 alpha(fl/fl) littermates, p38 alpha(Delta Hep) mice developed significant nutritional steatohepatitis induced by HFD, HFHC or MCD. Meanwhile, p38 alpha(Delta M Phi) mice exhibited less severe steatohepatitis and insulin resistance than p38 alpha(fl/fl) mice in response to a HFHC or MCD. The effect of macrophage p38 alpha in promoting steatohepatitis was mediated by the induction of pro-inflammatory factors (CXCL2, IL-1 beta, CXCL10 and IL-6) secreted by M1 macrophages and associated signaling pathways. p38 alpha(Delta M Phi) 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 p38 alpha(Delta M Phi) mice showed decreased steatosis and inflammatory damage. In a co-culture system, p38 alpha deleted macrophages attenuated steatohepatitic changes in hepatocytes through decreased secretion of pro-inflammatory cytokines (TNF-alpha, CXCL10 and IL-6), which mediate M1 macrophage polarization in p38 alpha(Delta M Phi) mice. Restoration of TNF-zeta, CXCL10 or IL-6 induced lipid accumulation and inflammatory responses in p38 alpha(fl/fl) hepatocytes co-cultured with p38 alpha(Delta M Phi) macrophages. Moreover, pharmacological p38 inhibitors suppressed HFHC-induced steatohepatitis. Conclusions: Macrophage p38 alpha promotes the progression of steatohepatitis by inducing pro-inflammatory cytokine secretion and M1 polarization. p38 inhibition protects against steatohepatitis. Lay summary: p38 mitogen-activated protein kinases are important inflammatory factors. In the present study, we demonstrated that p38 alpha is upregulated in liver tissues of patients with non-alcoholic fatty liver diseases. Genetic deletion of p38 alpha in macrophages led to ameliorated nutritional steatohepatitis in mice through decreased pro-inflammatory cytokine secretion and increased M2 macrophage polarization. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V.