Deletion of unwantedand damaged cells is an essential component of tissue homeostasis, remodeling and development and the mechanism by which inflammation is resolved duringthe return to normal structureand function. We earlier showed that externalized phosphatidylserine (PS) contributes to engulfment of apoptotic cells, and is critical to the anti-inflammatory and anti-immunogenic sequelae. We have recently identified a second uptake pathway resulting from ligation of the internalization receptor, CD91(LRP)by calreticulih expressed on the apoptotic cell surface. Furthermore, in the absence of """"""""don't eat me"""""""" signals such as the CD47-SIRPa combination, even viable cells are engulfed, suggesting the additional need to inactivate these on apoptotic cells before they can be ingested. The removal pathways are highly conserved evolutionary, are found in most cell types and appear to involveuniquesignaling pathways and mechanisms of uptake.A large number of potential receptors, bridge molecules and intracellular processes have been implicated apoptotic cell uptake (a process we are calling efferocytosis). We suggest that the time is ripe to integrate and clarify the roles of these disparate systems. By building on the PS recognition and LRP-driven uptake mechanisms as a base, this renewal application has brought two grants together and sets a framework around which the ingestion mechanisms can be pieced together and some of the other implicated molecules and processes (for example thrombospondin and the role of cell adhesion) can be placed. We hypothesize that in normal removal, both the PS recognition and LRP are involved, interacting together to achieve a controlled and balanced engulfment, regulated in part by competing activation of Rac-1 and RhoA. Approaches includeuse of knockout cells and animals, molecular modification, biochemistry and cell biology and an extensive collaborative network.
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