Macrophage p38α promotes nutritional steatohepatitis through M1 polarization.

Background & 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 (p38α), macrophage-specific p38α knockout (p38α) and wild-type (p38α) 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 p38α littermates, p38α mice developed significant nutritional steatohepatitis induced by HFD, HFHC or MCD. Meanwhile, p38α mice exhibited less severe steatohepatitis and insulin resistance than p38α 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. p38α mice exhibited M2 anti-inflammatory polarization as demonstrated by increased CD45F4/80CD11bCD206 M2 macrophages and enhanced arginase activity in liver tissues. Primary hepatocytes from p38α 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 p38α mice. Restoration of TNF-α, CXCL10 or IL-6 induced lipid accumulation and inflammatory responses in p38α hepatocytes co-cultured with p38α 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. LAY SUMMARY: p38 mitogen-activated protein kinases are important inflammatory factors. In the present study, we demonstrated that p38α is upregulated in liver tissues of patients with non-alcoholic fatty liver diseases. Genetic deletion of p38α in macrophages led to ameliorated nutritional steatohepatitis in mice through decreased pro-inflammatory cytokine secretion and increased M2 macrophage polarization.