2. Academic Validation
  3. Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release

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

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. ravi@virginia.edu.
  • 11 Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA. ravi@virginia.edu.
  • 12 Inflammation Research Centre, VIB, and Department of Biomedical Molecular Biology, Ghent, Belgium. ravi@virginia.edu.
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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