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Interpreting an apoptotic corpse as anti-inflammatory involves a chloride sensing pathway

Research output: Contribution to journalArticle

  • Justin S A Perry
  • Sho Morioka
  • Christopher B Medina
  • J Iker Etchegaray
  • Brady Barron
  • Michael H Raymond
  • Christopher Lucas
  • Suna Onengut-Gumuscu
  • Eric Delpire
  • Kodi S. Ravichandran

Related Edinburgh Organisations

Original languageEnglish
JournalNature Cell Biology
DOIs
Publication statusPublished - 2 Dec 2019

Abstract

Phagocytes in different tissues recognize and remove apoptotic cells via the process ofefferocytosis. Although it is well-established that efferocytosis elicits an anti-inflammatoryresponse by phagocytes, the molecules and mechanisms that enforce this response in phagocytesare still being defined. In attempting to decipher gene programs induced after a phagocyteingests a dying cell, we uncovered a chloride-sensing signaling pathway that controls both the‘appetite’ of a phagocyte and how a phagocyte responds after corpse uptake. First, we noted thatwithin phagocytes that have ingested a corpse, the solute carrier12 (SLC12) family membersSLC12A2 and SLC12A4 are actively modulated. Interfering with SLC12A2, either geneticallyor pharmacologically, led to significantly enhanced corpse uptake per phagocyte, while loss ofSLC12A4 inhibited corpse uptake. Interestingly, when phagocytes with disrupted SLC12A2engulfed apoptotic corpses, the typical homeostatic efferocytosis signature was perturbed,characterized by loss of the canonical anti-inflammatory program and replaced by pro-inflammatory and oxidative stress-associated gene programs. In mechanistic studies,efferocytosis was also regulated by the chloride-sensing pathway upstream of SLC12A2,including the kinases WNK1-OSR1-SPAK, and this involved chloride entry/exit across theplasma membrane of phagocytes during corpse engulfment, and contributes to enhanced corpsebinding to Slc12a2-deficient phagocytes. We also show that the ‘switch’ to pro-inflammatorysensing of apoptotic cells is specifically due to disruption of the chloride-sensing pathway andnot due to corpse overload or poor degradation, and that the pro-inflammatory gene signature canbe reversed using a chloride ionophore. Collectively, these data identify the WNK1-OSR1-SPAK-SLC12A2/SLC12A4 chloride-sensing pathway and chloride flux in phagocytes as keymodifiers of how a phagocyte interprets the engulfed apoptotic corpse.


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