|ZFIN ID: ZDB-PUB-190606-9|
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Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release
Morioka, S., Perry, J.S.A., Raymond, M.H., Medina, C.B., Zhu, Y., Zhao, L., Serbulea, V., Onengut-Gumuscu, S., Leitinger, N., Kucenas, S., Rathmell, J.C., Makowski, L., Ravichandran, K.S.
|Source:||Nature 563: 714-718 (Journal)|
|Registered Authors:||Kucenas, Sarah, Zhu, Yunlu|
|PubMed:||30464343 Full text @ Nature|
Morioka, S., Perry, J.S.A., Raymond, M.H., Medina, C.B., Zhu, Y., Zhao, L., Serbulea, V., Onengut-Gumuscu, S., Leitinger, N., Kucenas, S., Rathmell, J.C., Makowski, L., Ravichandran, K.S. (2018) Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release. Nature. 563:714-718.
ABSTRACTDevelopment 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.