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 - 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 -