Regulation of the Macrophage-Hepatic Stellate Cell Interaction by Targeting Macrophage Peroxisome Proliferator-Activated Receptor Gamma to Prevent Non-Alcoholic Steatohepatitis Progression in Mice.

Background & Aims Macrophages display remarkable plasticity and can interact with surrounding cells to affect hepatic immunity and tissue remodelling during the progression of liver diseases. Peroxisome proliferator-activated receptor gamma (PPAR gamma) plays a critical role in macrophage maturation, polarization and metabolism. In this study, we investigated the role of PPAR gamma in macrophage-hepatic stellate cell (HSC) interaction during non-alcoholic steatohepatitis (NASH) development. Methods Wild-type, Pparg(fl/fl) and Pparg(Delta Lyz2) mice were fed a methionine- and choline-deficient (MCD) diet to induce NASH. Depletion of macrophages was performed using an injection of gadolinium chloride intraperitoneally. PPAR gamma-overexpressing or PPAR gamma-knockout macrophages were stimulated with saturated fatty acid (SFA) and cocultured with HSCs in a conditioned medium or the transwell coculture system. Results Depletion of macrophages inhibited HSC activation and ameliorated NASH progression in MCD diet-fed mice. Coculturing HSCs with macrophages or culturing HSCs in a macrophage-conditioned medium-facilitated HSC activation, and this effect was magnified when macrophages were metabolically activated by SFA. Moreover, the absence of PPAR gamma in macrophages enhanced metabolic activation, promoting the migration and activation of HSCs through IL-1 beta and CCL2. In contrast, overexpression of PPAR gamma in macrophages obtained the opposite effects. In vivo, macrophage-specific PPAR gamma knockout affected the phenotype of hepatic macrophages and HSCs, involving the MAPK and NLRP3/caspase-1/IL-1 beta signalling pathways. Infiltrating hepatic monocyte-derived macrophages became the predominant macrophages in NASH liver, especially in Pparg(Delta Lyz2) mice, paralleling with aggravated inflammation and fibrosis. Conclusions Regulating macrophage PPAR gamma affected the metabolic activation of macrophages and their interaction with HSCs. Macrophage-specific PPAR gamma may be an attractive therapeutic target for protecting against NASH-associated inflammation and fibrosis.