Differential reprogramming of macrophage efferocytosis by apoptotic and necrotic cells 3524

Abstract Description Effective apoptotic cell clearance (efferocytosis) is carried out by macrophages. Efficient efferocytosis is critical for inflammation resolution and limits tissue damage. Here, we examine how uptake of apoptotic or necrotic corpses modulates efferocytosis and inflammation, hypothesizing the type of dying corpse is critical therein. We find efferocytosis rates are similar between corpse types, necrotic corpse uptake enhances lysosomal acidification. Surprisingly, while apoptotic corpses generally suppress liposaccharide-induced pro-inflammatory cytokine release phosphatidylserine dependently, subsets of cytokines associated with inflammasome and Th1 activation were augmented. Blocking uptake of necrotic corpses dramatically augmented inflammation. Continual efferocytosis is phosphatidylserine dependent and inhibited by prior necrotic corpse uptake. This inhibition is conserved among macrophage types. Altogether, these data challenge the concept that efferocytosis is strictly immunosuppressive, demonstrate differences in the immunosuppressive profile between corpses and indicate necrotic cells cannot efficiently promote continual efferocytosis. They further suggest pleiotropic effects of necrotic cells, including soluble factor release and continual efferocytosis inhibition, perpetuate inflammation. Transcriptomic analysis of macrophages after loading with corpses should reveal mechanistic insight into how necrotic cell uptake perturbs the resolution of inflammation. Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)