Lysosomal Cholesterol Hydrolysis Couples Efferocytosis to Anti-Inflammatory Oxysterol Production

Rationale: Macrophages face a substantial amount of cholesterol following the ingestion of apoptotic cells and the lysosomal acid lipase (LIPA) has a major role in hydrolyzing cholesteryl esters in the endocytic compartment. Objective: Here, we directly investigated the role of LIPA-mediated clearance of apoptotic cells both in vitro and in vivo. Methods and Results: We show that LIPA inhibition causes a defective efferocytic response due to impaired generation of 25-OHC and 27-OHC. Reduced synthesis of 25-OHC after LIPA inhibition contributed to defective mitochondria associated membrane (MAM) leading to mitochondrial oxidative stress-induced NLRP3 inflammasome activation and caspase 1-dependent Rac1 degradation. A secondary event consisting of failure to appropriately activate liver X receptor-mediated pathways led to mitigation of cholesterol efflux and apoptotic cell clearance. In mice, LIPA inhibition caused defective clearance of apoptotic lymphocytes and stressed erythrocytes by hepatic and splenic macrophages, culminating in splenomegaly and splenic iron accumulation under hypercholesterolemia. Conclusions: Our findings position lysosomal cholesterol hydrolysis as a critical process that prevents metabolic inflammation by enabling efficient macrophage apoptotic cell clearance.