GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain

The mechanisms of pain induction by inflammation have been extensively studied. However, the mechanisms of pain resolution are not fully understood. Here, we report that GPR37, expressed by macrophages (M Phi s) but not microglia, contributes to the resolution of inflammatory pain. Neuroprotectin D1 (NPD1) and prosaptide TX14 increase intracellular Ca2+ (iCa(2+)) levels in GPR37-transfected HEK293 cells. NPD1 and TX14 also bind to GPR37 and cause GPR37-dependent iCa(2+) increases in peritoneal MFs. Activation of GPR37 by NPD1 and TX14 triggers M Phi phagocytosis of zymosan particles via calcium signaling. Hind paw injection of pH-sensitive zymosan particles not only induces inflammatory pain and infiltration of neutrophils and M Phi s, but also causes GPR37 upregulation in M Phi s, phagocytosis of zymosan particles and neutrophils by M Phi s in inflamed paws, and resolution of inflammatory pain in WT mice. Mice lacking Gpr37 display deficits in M Phi phagocytic activity and delayed resolution of inflammatory pain. Gpr37-deficient M Phi s also show dysregulations of proinflammatory and antiinflammatory cytokines. MF depletion delays the resolution of inflammatory pain. Adoptive transfer of WT but not Gpr37-deficient M Phi s promotes the resolution of inflammatory pain. Our findings reveal a previously unrecognized role of GPR37 in regulating M Phi phagocytosis and inflammatory pain resolution.