Abstract Tu0034: Chimeric Efferocytic Receptors Boost Efferocytosis and Ameliorate Cardiovascular Diseases

The efficient clearance of dying apoptotic cells through efferocytosis is critical for resolving inflammation and ameliorating tissue damage in various cardiovascular diseases (CVD). For example, defective efferocytosis is a key driver of destabilizing necrotic core formation in atherosclerotic plaque. Boosting the efferocytic capacity of phagocytic cells may therefore represent a successful strategy for treating CVD. We recently engineered chimeric efferocytic receptor TELMO — a novel fusion receptor that possesses the phosphatidylserine binding domain of the efferocytosis receptor TIM4 fused to the signaling domain of adapter protein ELMO1 — and demonstrated that it enhances efferocytosis in non-professional phagocytes. However, it is unclear whether TELMO can be applied to improve macrophage efferocytosis and cardiovascular outcomes in vivo . Here, we assessed the hypothesis that enhancing efferocytosis through TELMO expression would reduce atherosclerotic plaque burden and ameliorate the sequalae of myocardial ischemia-reperfusion injury using two complementary mouse models of CVD. First, we found that mice expressing TELMO in myeloid cells have a significant reduction in atherosclerotic plaque burden compared to WT littermate controls (Whole Artery Plaque Area: TELMO 4.9% vs. WT 9.8%, p=0.008) following administration of AAV8-mPCSK9 and 16 weeks of high fat diet feeding without differences in levels of plasma cholesterol or triglycerides. Similarly, mice expressing TELMO in myeloid cells demonstrated improved ejection fraction (Ejection Fraction: TELMO 47.4% vs. WT 37.0%, p=0.028) and reduced fibrosis 4 weeks following cardiac ischemia-reperfusion injury. Together, our results suggest that TELMO possesses dual therapeutic potential by slowing atherosclerotic disease progression as well as improving post-myocardial infarction tissue repair. Additional tissue and cellular mechanistic studies are currently underway to investigate how TELMO-mediated boosting of efferocytosis affects myeloid cell fate specification and phenotypes in both disease contexts.