Histones present on the surface of late apoptotic cells 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 and that 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 in late apoptotic cells. The phagocytosis of late apoptotic cells by either professional or nonprofessional phagocytes is enhanced when histones are present on the surface of dead cells. Thus, histones serve as "eat-me" signals to induce the phagocytosis of dead cells. In RAGE-knockout cells, the phagocytosis of late apoptotic cells was not influenced by the removal of histones, indicating that RAGE is required for the removal of histone-presenting cells. In RAGE-knockout mice, wound healing and removal of dead cells from wound sites are delayed, suggesting that RAGE-mediated phagocytosis functions under physiological conditions.