Tim4- and MerTK-Mediated Engulfment of Apoptotic Cells by Mouse

Apoptotic cells are swiftly engulfed bymacrophages to prevent the release of noxiousmaterials fromdying cells. Apoptotic cells expose phosphatidylserine (PtdSer) on their surface, andmacrophages engulf themby recognizing PtdSer using specific receptors and op-sonins.Here, we found thatmouse resident peritonealmacrophages expressingTim4 andMerTKare highly efficient at engulfing apoptotic cells. Neutralizing antibodies against either Tim4orMerTK inhibited themacrophage engulfment of apoptotic cells.Tim4-nullmacrophages exhibited reduced binding and engulfment of apoptotic cells, whereasMerTK-nullmacrophages retained the ability to bind apoptotic cells but failed to engulf them. The incubation ofwild-type peritonealmacrophageswith apoptotic cells induced the rapid tyrosine phosphorylation ofMerTK,whichwas not observedwithTim4-nullmacrophages.WhenmouseBa/F3 cells were trans-formedwithTim4, apoptotic cells bound to the transformants butwere not engulfed. Transformation of Ba/F3 cells withMerTKhad no effect on the binding or engulfment of apoptotic cells; however, Tim4/MerTK transformants exhibited strong engulfment activity. Taken together, these results indicate that the engulfment of apoptotic cells by resident peritonealmacrophages proceeds in two steps: binding toTim4, a PtdSer receptor, followed byMerTK-mediated cell engulfment. Millions of harmful, useless, or senescent cells in our bodyundergo apoptosis every minute and are swiftly engulfed by macrophages for clearance (1, 2). Engulfment is required to pre-vent apoptotic cells from undergoing secondary necrosis and re-leasing noxious materials. Inefficient engulfment of apoptoti