Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein

Abstract

When a phagocyte engulfs a dying cell, it essentially doubles its cellular contents, yet phagocytes are capable of ingesting several apoptotic cells one after the other. The factors regulating this impressive engulfment capacity are not well understood. Kodi Ravichandran and colleagues show here that the mitochondrial membrane protein Ucp2, which is known to be linked to metabolic diseases and atherosclerosis, is critically important to engulfment capacity. Rapid and efficient removal of apoptotic cells by phagocytes is important during development, tissue homeostasis and in immune responses1,2,3,4,5. Efficient clearance depends on the capacity of a single phagocyte to ingest multiple apoptotic cells successively, and to process the corpse-derived cellular material6. However, the factors that influence continued clearance by phagocytes are not known. Here we show that the mitochondrial membrane potential of the phagocyte critically controls engulfment capacity, with lower potential enhancing engulfment and vice versa. The mitochondrial membrane protein Ucp2, which acts to lower the mitochondrial membrane potential7,8,9, was upregulated in phagocytes engulfing apoptotic cells. Loss of Ucp2 reduced phagocytic capacity, whereas Ucp2 overexpression enhanced engulfment. Mutational and pharmacological studies indicated a direct role for Ucp2-mediated mitochondrial function in phagocytosis. Macrophages from Ucp2-deficient mice10,11 were impaired in phagocytosis in vitro, and Ucp2-deficient mice showed profound in vivo defects in clearing dying cells in the thymus and testes. Collectively, these data indicate that mitochondrial membrane potential and Ucp2 are key molecular determinants of apoptotic cell clearance. As Ucp2 is linked to metabolic diseases and atherosclerosis11,12, this newly discovered role for Ucp2 in apoptotic cell clearance has implications for the complex aetiology and pathogenesis of these diseases.