Lipid droplet efferocytosis attenuates proinflammatory signaling in macrophages via TREM2 and MS4A7-dependent mechanisms

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by the injury of steatotic hepatocytes, triggering the release of endogenous danger-associated molecular patterns (DAMP). The nature of the danger signals and their role in engaging the innate immune cells like macrophage remain to be fully delineated. Recent work demonstrated that exposed lipid droplets (LD) serve as a disease-associated danger signal that promotes monocyte infiltration and its maturation into TREM2+ macrophages within the MASH liver. In this study, we explored the nature of LD-mediated danger signaling and its impact on inflammatory signaling in macrophages. We found that efferocytosis of LDs triggers a global transcriptional response and dampens pro-inflammatory signaling in cultured macrophages. LD treatments attenuated proinflammatory signaling and NLRP3 inflammasome activation via mechanisms independent of lipid hydrolysis by macrophages. TREM2 is required for the attenuation of inflammatory response, whereas MS4A7 downregulation contributes to the dampening effects of LD treatments. These results underscore the dual role of LD-mediating danger signaling in MASH liver by promoting monocyte infiltration and TREM2+ macrophage induction and dampening pro-inflammatory response in macrophages.