Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release

  • Nature. 2018 Nov;563(7733):714-718. doi: 10.1038/s41586-018-0735-5.
Sho Morioka  1  2 ,  Justin S A Perry  1  2 ,  Michael H Raymond  1  3 ,  Christopher B Medina  1  2 ,  Yunlu Zhu  4 ,  Liyang Zhao  5 ,  Vlad Serbulea  6 ,  Suna Onengut-Gumuscu  7 ,  Norbert Leitinger  6 ,  Sarah Kucenas  4 ,  Jeffrey C Rathmell  8 ,  Liza Makowski  5  9 ,  Kodi S Ravichandran  10  11  12
Affiliations
  • 1. The Center for Cell Clearance, University of Virginia, Charlottesville, VA, USA.
  • 2. Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
  • 3. Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA.
  • 4. Department of Biology, University of Virginia, Charlottesville, VA, USA.
  • 5. Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA.
  • 6. Department of Pharmacology, University of Virginia, Charlottesville, VA, USA.
  • 7. Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
  • 8. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 9. Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
  • 10. The Center for Cell Clearance, University of Virginia, Charlottesville, VA, USA. [email protected].
  • 11. Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA. [email protected].
  • 12. Inflammation Research Centre, VIB, and Department of Biomedical Molecular Biology, Ghent, Belgium. [email protected].
PMID: 30464343 DOI: 10.1038/s41586-018-0735-5
Abstract

Development and routine tissue homeostasis require a high turnover of apoptotic cells. These cells are removed by professional and non-professional phagocytes via efferocytosis1. How a phagocyte maintains its homeostasis while coordinating corpse uptake, processing ingested Materials and secreting anti-inflammatory mediators is incompletely understood1,2. Here, using RNA Sequencing to characterize the transcriptional program of phagocytes actively engulfing apoptotic cells, we identify a genetic signature involving 33 members of the solute carrier (SLC) family of membrane transport proteins, in which expression is specifically modulated during efferocytosis, but not during antibody-mediated phagocytosis. We assessed the functional relevance of these SLCs in efferocytic phagocytes and observed a robust induction of an aerobic glycolysis program, initiated by SLC2A1-mediated glucose uptake, with concurrent suppression of the Oxidative Phosphorylation program. The different steps of phagocytosis2-that is, 'smell' ('find-me' signals or sensing factors released by apoptotic cells), 'taste' (phagocyte-apoptotic cell contact) and 'ingestion' (corpse internalization)-activated distinct and overlapping sets of genes, including several SLC genes, to promote glycolysis. SLC16A1 was upregulated after corpse uptake, increasing the release of lactate, a natural by-product of aerobic glycolysis3. Whereas glycolysis within phagocytes contributed to actin polymerization and the continued uptake of corpses, lactate released via SLC16A1 promoted the establishment of an anti-inflammatory tissue environment. Collectively, these data reveal a SLC program that is activated during efferocytosis, identify a previously unknown reliance on aerobic glycolysis during apoptotic cell uptake and show that glycolytic by-products of efferocytosis can influence surrounding cells.

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