title: Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein.
abstract: Rapid and efficient removal of apoptotic cells by phagocytes is important during development, tissue homeostasis and in immune responses. Efficient clearance depends on the capacity of a single phagocyte to ingest multiple apoptotic cells successively, and to process the corpse-derived cellular material. 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 potential, 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 mice 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, this newly discovered role for Ucp2 in apoptotic cell clearance has implications for the complex aetiology and pathogenesis of these diseases.
authors.affiliation: Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Daeho
authors.initials: D
authors.lastname: Park
authors.forename: Claudia Z
authors.initials: CZ
authors.lastname: Han
authors.forename: Michael R
authors.initials: MR
authors.lastname: Elliott
authors.forename: Jason M
authors.initials: JM
authors.lastname: Kinchen
authors.forename: Paul C
authors.initials: PC
authors.lastname: Trampont
authors.forename: Soumita
authors.initials: S
authors.lastname: Das
authors.forename: Sheila
authors.initials: S
authors.lastname: Collins
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Lysiak
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Hoehn
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D007473:Ion Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010586:Phagocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology; D000071246:Uncoupling Protein 2
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2