Apoptosis leads to immediate removal of cells from the body during development, tissue remodeling, maturation of the immune system or resolution of inflammation. Surface changes on the apoptotic cells are recognized by neighboring cells including fibroblasts or professional phagocytes such as macrophages and result in their engulfment and digestion. It is suggested that collectin family members (e.g. mannose binding protein, SPA, SPD or C1q) participate actively in this recognition and removal by binding to multiple structures on the apoptotic cells (especially on membrane blebs) and by initiating uptake into the phagocytes through interaction of their collagenous "tails" with cell surface calreticulin. The uptake process is suggested to occur by macropinocytosis and to be functionally different from that initiated via Fc receptor engagement. It is further proposed that calreticulin-mediated macropinocytotic mechanisms could account for some of the suggested roles for collectins in innate immunity. Apoptotic cells or surrogate particles (erythrocytes with surface-bound collectins, collectin fragments or ligands for caireticulin) will be examined for uptake and the role of calreticulin determined. The ability of these ligands to initiate macropinocytosis (stimulated or triggered phagocytosis) will be examined and contrasted to uptake through the Fc receptor (zipper mechanism). Upstream signaling pathways induced by calreticulin ligation and aggregation will be addressed as will some questions as to how the molecule reaches the cell surface. The binding of collectins to apoptotic cell surfaces and surface structures will focus in particular on known alterations in phospholipid distribution on these cells. Finally, the role of collectins and calreticulin in removal of apoptotic cells and cell debris will be examined in the inflamed peritoneum and lung using inhibitors and knockout mice.

R01GM048211

1993-05-01

2006-04-30