GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain

Abstract

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 (MΦs) but not microglia, contributes to the resolution of inflammatory pain. Neuroprotectin D1 (NPD1) and prosaptide TX14 increase intracellular Ca2+ (iCa2+) levels in GPR37-transfected HEK293 cells. NPD1 and TX14 also bind to GPR37 and cause GPR37-dependent iCa2+ increases in peritoneal MΦs. Activation of GPR37 by NPD1 and TX14 triggers MΦ 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 MΦs, but also causes GPR37 upregulation in MΦs, phagocytosis of zymosan particles and neutrophils by MΦs in inflamed paws, and resolution of inflammatory pain in WT mice. Mice lacking Gpr37 display deficits in MΦ phagocytic activity and delayed resolution of inflammatory pain. Gpr37-deficient MΦs also show dysregulations of proinflammatory and antiinflammatory cytokines. MΦ depletion delays the resolution of inflammatory pain. Adoptive transfer of WT but not Gpr37-deficient MΦs promotes the resolution of inflammatory pain. Our findings reveal a previously unrecognized role of GPR37 in regulating MΦ phagocytosis and inflammatory pain resolution.

Protective effects of GPR37 via regulation of inflammation and multiple cell death pathways after ischemic stroke in mice

“…Several potential ligands for GPR37 have been reported, including prosaposin and its active fragment prosaptide (17)(18)(19), an invertebrate peptide called head activator that is structurally similar to prosaptide (20,21), and the bioactive lipid neuroprotectin-1 (22). There is not yet a broad consensus as to whether any or all of these ligands represent authentic endogenous ligands for GPR37, and further studies in vivo will be necessary to address this important question.…”

“…Several ligands have been reported for GPR37, although a consensus has not yet been achieved as to whether any or all of these ligands are authentic endogenous agonists. The reported ligands for GPR37 include prosaposin and its active fragment prosaptide (17)(18)(19), an invertebrate peptide related to prosaptide known as head activator peptide (20,21), and the lipid metabolite neuroprotectin D1 (22). Intriguingly, both prosaptide (23)(24)(25) and neuroprotectin D1 (26)(27)(28) have been reported to exert protective actions in rodent models of nerve injury or stroke.…”

Resolution of inflammation: Role of B cells

“…These receptors are expressed in different cell types and tissues, giving rise to tissue specificity. The current known specific SPM receptors in human and mouse include ALX/FPR2, which is activated by RvD1, RvD3, and LXA 4 , ChemR23/ERV1 activated by Resolvin E1 (RvE1) and Resolvin E2 (RvE3), DRV1 (orphan receptor GPR32) by RvD1, DRV2 (orphan receptor GPR18) by Resolvin D2 (RvD2), and GPR37 by PD1 . GPR37 plays an essential role in PD1‐stimulated Mϕ phagocytosis and the resolution of inflammatory pain .…”

Accelerating the reversal of inflammatory pain with NPD1 and its receptor GPR37

“…Until now, however, the receptor that mediates the proresolving actions of NPD1 has remained undefined. In this issue, Bang et al identify GPR37 (parkin-associated endothelin-like receptor/Pael-R) as a receptor for NPD1 and provide evidence implicating GPR37 as a new molecular participant in macrophage phagocytosis and the resolution of inflammatory pain (13). NPD1, GPR37, and the resolution of inflammatory pain GPR37 is a GPCR most extensively studied in the brain that has been associated with Parkinson's disease and autism spectrum disorder (14)(15)(16).…”

“…Moreover, the expression and function of GPR37 in immune cells has not been previously addressed. To explore potential roles for GPR37 in inflammatory pain, Bang et al characterized the cellular distribution of GPR37 in mouse hind paw skin, dorsal root ganglia (DRG, which house sensory neuron cell bodies), the spinal cord, and the brain (13). They detected GPR37 expression in a subset of macrophages in skin, peritoneal fluid, and DRG.…”