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

Daeho Park, Claudia Z. Han, Michael R. Elliott, Jason M. Kinchen, Paul C. Trampont, Soumita Das, Sheila Collins, Jeffrey J. Lysiak, Kyle L. Hoehn, Kodi S. Ravichandran

Research output: Contribution to journalArticlepeer-review

137 Scopus citations

Abstract

Rapid and efficient removal of apoptotic cells by phagocytes is important during development, tissue homeostasis and in immune responses1-5. 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 potential7-9, 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 atherosclerosis 11,12, this newly discovered role for Ucp2 in apoptotic cell clearance has implications for the complex aetiology and pathogenesis of these diseases.

Original languageEnglish
Pages (from-to)220-224
Number of pages5
JournalNature
Volume477
Issue number7363
DOIs
StatePublished - Sep 8 2011

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