Histone serves as an eat-me signal to induce RAGE-mediated phagocytosis

The receptor for advanced glycation end products (RAGE) is a multiligand receptor that can induce phagocytosis in both professional and nonprofessional phagocytes. We found that histones are another ligand for RAGE. Binding between histones and RAGE is increased when DNA is attached to histones. While histones are chromosomal proteins in healthy cells, they are exposed to the cell surface as a complex with DNA when cells undergo apoptosis. The phagocytosis of apoptotic cells by either professional or nonprofessional phagocytes is enhanced when histones are present on the surface of apoptotic cells. Thus, histones serve as eat-me signals. In RAGE knockout cells, the phagocytosis of apoptotic cells was not influenced by the removal of histones, indicating that RAGE is required for the removal of histones from histone-presenting cells. In RAGE knockout mice, wound healing and removal of apoptotic cells from wound sites are delayed, suggesting that RAGE-mediated phagocytosis functions under physiological conditions.