Targeting Trem2 in Atherosclerosis Progression

PROJECT SUMMARY Atherosclerosis is driven by the deposition of low-density lipoprotein (LDL) cholesterol within the aortic intima, forming a plaque. During plaque formation, monocytes infiltrate the sites of atherosclerotic lesions where they differentiate into highly heterogeneous macrophage populations, including lipid-loaded “foamy” macrophages which are a primary contributor to plaque progression. Foamy macrophages are defined by their expression of Triggering Receptor Expressed on Myeloid Cells 2 (Trem2), a known lipid sensor and key modulating factor of atherosclerosis disease outcomes. Recent findings from our lab implicated Trem2 as a key factor modulating atherosclerosis disease progression in vivo. We found that Trem2 mediated foam cell formation, and conditional deletion of Trem2 in myeloid cells resulted in increased foam cell death, reduced macrophage proliferation, and reduced plaque size. This study was followed by a Trem2 agonism approach, where we found that stimulating Trem2 signaling enhanced atherosclerotic lesion burden. Using a Trem2 blocking antibody, I will test the hypothesis that Trem2 blockade attenuates atherosclerotic plaque progression by limiting macrophage lipid uptake and maintaining cell function. Next, I will tease apart the molecular signaling downstream of Trem2 that mediates foamy macrophage formation. Ultimately, the proposed aims will determine mechanisms of Trem2 signaling that reprogram foamy macrophage function and illuminate the therapeutic potential of a Trem2 blocking antibody in atherosclerosis.