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

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

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


Apoptotic cell clearance (efferocytosis) elicits an anti-inflammatory response by phagocytes, but the mechanisms that underlie this response are still being defined. Here, we uncover a chloride-sensing signalling pathway that controls both the phagocyte ‘appetite’ and its anti-inflammatory response. Efferocytosis transcriptionally altered the genes that encode the solute carrier (SLC) proteins SLC12A2 and SLC12A4. Interfering with SLC12A2 expression or function resulted in a significant increase in apoptotic corpse uptake per phagocyte, whereas the loss of SLC12A4 inhibited corpse uptake. In SLC12A2-deficient phagocytes, the canonical anti-inflammatory program was replaced by pro-inflammatory and oxidative-stress-associated gene programs. This ‘switch’ to pro-inflammatory sensing of apoptotic cells resulted from the disruption of the chloride-sensing pathway (and not due to corpse overload or poor degradation), including the chloride-sensing kinases WNK1, OSR1 and SPAK—which function upstream of SLC12A2—had a similar effect on efferocytosis. Collectively, the WNK1–OSR1–SPAK–SLC12A2/SLC12A4 chloride-sensing pathway and chloride flux in phagocytes are key modifiers of the manner in which phagocytes interpret the engulfed apoptotic corpse.

Original languageEnglish
Pages (from-to)1532-1543
Number of pages12
JournalNature Cell Biology
Issue number12
StatePublished - Dec 1 2019


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