Macrophage Trem2 Dampens Inflammation and Protects the Liver against NASH
Non-alcoholic fatty liver disease affects nearly 30% of people in the US encompassing a wide spectrum of pathogenesis from fatty liver to non-alcoholic steatohepatitis (NASH). During NASH, there is an influx of monocyte-derived macrophages, which are traditionally considered inflammatory. However, a subset of these macrophages, known as lipid associated macrophages (LAMs) have a high expression of triggering receptor expressed on myeloid cells 2 (Trem2), and have been found to play a protective role during obesity and NASH. We sought to elucidate the potential mechanisms by which these macrophages ameliorate NASH pathogenesis. We hypothesized that Trem2 confers a protective effect during NASH by reducing the ability of macrophages to incite hepatic inflammation. To test this hypothesis, we generated bone marrow-derived macrophages (BMDMs) from wild type (WT) and Trem2 knockout (KO) mice. We first confirmed the absence of Trem2 expression in the knockout BMDMs. Subsequently, we exposed BMDMs to palmitate, a long-chain fatty acid, to simulate the lipid-rich liver environment during NASH. RT-PCR analysis revealed increased gene expression of inflammatory cytokines IL-6 and IL-1𝛽 in palmitate-treated Trem2 KO BMDMs. Additionally, flow cytometry demonstrated a decrease in BODIPY staining in these cells, indicating reduced neutral lipid content compared to Trem2-sufficient cells. To determine the in vivo effects of Trem2 deficiency, Trem2 knockout mice were put on a high-fat high-carbohydrate diet for 12 weeks to induce NASH. Although there was no difference in body weight or liver weight between the Trem2 KO and WT mice, Trem2 KO mice showed higher serum aspartate transaminase (AST), a marker of hepatitis or liver cirrhosis, and higher liver triglyceride content. Additionally, Trem2 KO mice displayed a decrease in hepatic F4/80hi CD11bint macrophages and a subset of F4/80hi, monocyte-derived Kupffer cells compared to the WT mice. Collectively, our findings suggest that Trem2 contributes to NASH protection by dampening macrophage mediated inflammation and enhancing lipid clearance in the liver.