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

Nature volume 477, pages 220–224 (2011)Cite this article

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Abstract

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.

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Figure 1: Modulation of mitochondrial membrane potential and Ucp2 during engulfment.
Figure 2: Ucp2 overexpression promotes continued uptake of apoptotic cells.
Figure 3: Ucp2 links mitochondrial membrane potential to engulfment of apoptotic cells.
Figure 4: Impaired clearance of apoptotic cells in Ucp2 -deficient mice.

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Acknowledgements

We thank M. Schwartz and members of the K.S.R. laboratory for discussions. This work was supported by grants from the National Institute of General Medical Sciences (to K.S.R.), and ARRA funding from National Institute of Child Health and Development (to J.J.L. and K.S.R.). K.S.R. is a Bill Benter Senior Fellow of the American Asthma Foundation. J.M.K. is supported by an American Heart Association Award.

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Authors and Affiliations

  1. Center for Cell Clearance, University of Virginia, Charlottesville, 22908, Virginia, USA

    Daeho Park, Claudia Z. Han, Michael R. Elliott, Jason M. Kinchen, Paul C. Trampont & Kodi S. Ravichandran

  2. Beirne B. Cater Center for Immunology Research, University of Virginia, Charlottesville, 22908, Virginia, USA

    Daeho Park, Claudia Z. Han, Michael R. Elliott, Jason M. Kinchen, Paul C. Trampont & Kodi S. Ravichandran

  3. Department of Microbiology, University of Virginia, Charlottesville, 22908, Virginia, USA

    Claudia Z. Han, Jason M. Kinchen & Kodi S. Ravichandran

  4. Department of Medicine, University of Virginia, Charlottesville, 22908, Virginia, USA

    Soumita Das

  5. Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, 32827, Florida, USA

    Sheila Collins

  6. Department of Urology, University of Virginia, Charlottesville, 22908, Virginia, USA

    Jeffrey J. Lysiak

  7. Department of Pharmacology and CVRC, University of Virginia, Charlottesville, 22908, Virginia, USA

    Kyle L. Hoehn

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  1. Daeho Park
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Contributions

D.P., C.Z.H., M.R.E., P.C.T., J.M.K., S.D., J.J.L. and K.L.H. designed and performed all of the experiments. S.C. provided advice and the Ucp2 knockout mice. K.S.R. helped in the design of many of the experiments and provided overall coordination. D.P., K.L.H. and K.S.R. wrote and edited the manuscript with input from other authors.

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Correspondence to Kodi S. Ravichandran.

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The authors declare no competing financial interests.

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Park, D., Han, C., Elliott, M. et al. Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein. Nature 477, 220–224 (2011). https://doi.org/10.1038/nature10340

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