[Abstract] 

hile defects in the removal of apoptotic cells are linked to multiple inflammatory diseases and defects in organogenesis, whether apoptotic cell clearance can be tunable in mammals in vivo is not known. Here, using complementary gain of function and loss of function genetic approaches for the phagocytic receptor BAI1, we reveal that modulating apoptotic cell clearance is possible in vivo, and that tuning up the levels of even a single receptor can be beneficial in a model of inflammation. First, mice lacking BAI1 had many uncleared corpses after apoptosis induction in three different tissue contexts (thymus, testes, and the colon), while the corollary, where mice were engineered to overexpress BAI1 had fewer apoptotic cells after similar tissue injury. In an acute colonic inflammation model, BAI1-deficient mice had more pronounced colitis with lower survival and many uncleared apoptotic cells within the colonic epithelium; in contrast, BAI1^Tg mice showed fewer apoptotic cells and attenuated disease based on multiple parameters. Remarkably, genetically tuning up BAI1 expression in the colonic epithelial cells and improving their uptake of apoptotic cells was sufficient to lower colonic inflammation. Collectively, these data provide a genetic proof-of-concept that regulating apoptotic cell clearance is achievable in vivo, with potential to regulate tissue inflammation in specific contexts.