Loss of myeloid Paired Immunoglobulin-like Receptor B promotes atherosclerosis through inhibition of autophagy and metabolic rewiring

PROJECT SUMMARY Cardiovascular disease (CVD) is the leading cause of death globally. The root cause of CVD is a chronic inflammatory disease of the arterial wall called atherosclerosis. A critical determinant of atherosclerosis is macrophage inflammatory phenotype. Within atherosclerosis, anti-inflammatory pathways are dysfunctional, which results in pro-inflammatory stimuli driving macrophage phenotype. We have identified Paired immunoglobulin-like receptor B (PirB) as a novel inhibitor of macrophage-mediated inflammation by facilitating apoptotic cell digestion and promoting mitochondrial function. The aims of this proposal will determine the mechanisms by which PirB inhibits inflammation through phagosomal and mitochondrial signaling pathways. We will use macrophages containing a lysosomal reporter to track phagosome maturation and cargo fate. Additionally, we will dissect the molecular mechanism by which PirB regulates mitochondrial metabolic function and signaling.