Apoptotic cell clearance by phagocytes

Macrophages and dendritic cells recognize not only microorganisms foreign to the body but also dying self-cells, which they eliminate by engulfment. This phenomenon prevents dying cells from releasing potentially harmful or immunogenic intracellular materials. We found that milk fat globule-EGF-factor 8 (MFG-E8) linked apoptotic cells and phagocytes, and promoted the phagocytosis of cell corpses. MFG-E8 is expressed in tingible body macrophages (TBM) in the germinal centers of the spleen and lymph nodes. In MFG-E8-deficient mice, a large number of apoptotic lymphocytes were associated with TBM but were not engulfed, indicating that MFG-E8 was involved in the clearance of apoptotic B cells by TBM. The MFG-E8-deficient mice developed splenomegaly and produced autoantibodies such as antinuclear antibodies as well as anti-DNA antibodies in an age-dependent manner. To further examine the consequences of failure in apoptotic cell clearance, we produced a recombinant MFG-E8 mutant protein (D89E), which had inhibitory effects on the phagocytosis of apoptotic cells by a wide variety of phagocytes. When intravenously injected into mice, the D89E protein induced the production of autoantibodies. The autoantibodies production was enhanced by the coinjection of syngeneic apoptotic thymocytes. These results indicated that the impairment of apoptotic cell phagocytosis led to autoantibody production.