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

Apoptotic cell clearance (efferocytosis) elicits an anti-inflammatory response by phagocytes, but the mechanisms underlying this response are still being defined. Here, we uncover a chloride-sensing signaling pathway that controls both the phagocyte appetite and its anti-inflammatory response. Efferocytosis transcriptionally altered the genes coding for solute carrier (SLC) proteins SLC12A2 and SLC12A4. Interfering with SLC12A2 expression or function led to significantly enhanced corpse uptake per phagocyte, while 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 was due to disruption of the chloride-sensing pathway (and not corpse overload or poor degradation,) and the chloride-sensing kinases WNK1-OSR1-SPAK that function upstream of SLC12A2 similarly affected efferocytosis. Collectively, the WNK1-OSR1-SPAK-SLC12A2/SLC12A4 chloride-sensing pathway and chloride flux in phagocytes act as key modifiers of how a phagocyte interprets the engulfed apoptotic corpse.