TY - JOUR
T1 - Interpreting an apoptotic corpse as anti-inflammatory involves a chloride sensing pathway
AU - Perry, Justin S.A.
AU - Morioka, Sho
AU - Medina, Christopher B.
AU - Iker Etchegaray, J.
AU - Barron, Brady
AU - Raymond, Michael H.
AU - Lucas, Christopher D.
AU - Onengut-Gumuscu, Suna
AU - Delpire, Eric
AU - Ravichandran, Kodi S.
N1 - Funding Information:
We thank members of the Ravichandran laboratory for discussions and reading of this manuscript. J.S.A.P. was supported by Cancer Research Institute—Mark Foundation Fellowship (NCI 1K99CA237728-01), a Burroughs Wellcome PDEP award and a NCI Cancer Research Training Award (5T32CA009109-39). S.M. is supported by grants from the Mishima-Kaiun Memorial Foundation and The Kanae Foundation for the Promotion of Medical Science. This research was supported by grants to K.S.R. from the NIGMS (GM064709), NIMH (MH096484), NHLBI (P01HL120840) and the Center for Cell Clearance at the University of Virginia, Pilot funding from the UVa Brain Institute, Odysseus I award from the FWO and an EOS grant from the FWO. E.D. is funded by NIH grants R21GM118944 and R01DK093501. C.B.M. is supported by the Pannexin Program Award through the NHLBI (P01HL120840). M.H.R. was supported by the UVA Neuroscience Training Program 4T32GM008328-25. J.I.E. is supported by NIAID Training Award 5T32AI007496. C.D.L. is supported by an award from The Wellcome Trust (206566/Z/17/Z). C.M. and B.B. have been supported by the NIH T32 Pharmacology Training Grant T32 GM00705.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85076063656&partnerID=8YFLogxK
U2 - 10.1038/s41556-019-0431-1
DO - 10.1038/s41556-019-0431-1
M3 - Article
C2 - 31792382
AN - SCOPUS:85076063656
SN - 1465-7392
VL - 21
SP - 1532
EP - 1543
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 12
ER -