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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 (M?s) 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 M?s. Activation of GPR37 by NPD1 and TX14 triggers M? 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?s, but also causes GPR37 upregulation in M?s, phagocytosis of zymosan particles and neutrophils by M?s in inflamed paws, and resolution of inflammatory pain in WT mice. Mice lacking Gpr37 display deficits in M? phagocytic activity and delayed resolution of inflammatory pain. Gpr37-deficient M?s also show dysregulations of proinflammatory and antiinflammatory cytokines. M? depletion delays the resolution of inflammatory pain. Adoptive transfer of WT but not Gpr37-deficient M?s promotes the resolution of inflammatory pain. Our findings reveal a previously unrecognized role of GPR37 in regulating M? phagocytosis and inflammatory pain resolution.

SUBMITTER: Bang S

PROVIDER: S-EPMC6063480 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain.

Bang Sangsu S Xie Ya-Kai YK Zhang Zhi-Jun ZJ Wang Zilong Z Xu Zhen-Zhong ZZ Ji Ru-Rong RR

The Journal of clinical investigation 20180716 8

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. Acti ...[more]

PMID: 30010619

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Project description:UnlabelledInsights into mechanisms governing resolution of inflammatory pain are of great importance for many chronic pain-associated diseases. Here we investigate the role of macrophages/monocytes and the anti-inflammatory cytokine interleukin-10 (IL-10) in the resolution of transient inflammatory pain. Depletion of mice from peripheral monocytes/macrophages delayed resolution of intraplantar IL-1β- and carrageenan-induced inflammatory hyperalgesia from 1 to 3 days to >1 week. Intrathecal administration of a neutralizing IL-10 antibody also markedly delayed resolution of IL-1β- and carrageenan-induced inflammatory hyperalgesia. Recently, we showed that IL-1β- and carrageenan-induced hyperalgesia is significantly prolonged in LysM-GRK2(+/-) mice, which have reduced levels of G-protein-coupled receptor kinase 2 (GRK2) in LysM(+) myeloid cells. Here we show that adoptive transfer of wild-type, but not of GRK2(+/-), bone marrow-derived monocytes normalizes the resolution of IL-1β-induced hyperalgesia in LysM-GRK2(+/-) mice. Adoptive transfer of IL-10(-/-) bone marrow-derived monocytes failed to normalize the duration of IL-1β-induced hyperalgesia in LysM-GRK2(+/-) mice. Mechanistically, we show that GRK2(+/-) macrophages produce less IL-10 in vitro. In addition, intrathecal IL-10 administration attenuated IL-1β-induced hyperalgesia in LysM-GRK2(+/-) mice, whereas it had no effect in wild-type mice. Our data uncover a key role for monocytes/macrophages in promoting resolution of inflammatory hyperalgesia via a mechanism dependent on IL-10 signaling in dorsal root ganglia.PerspectiveWe show that IL-10-producing monocytes/macrophages promote resolution of transient inflammatory hyperalgesia. Additionally, we show that reduced monocyte/macrophage GRK2 impairs resolution of hyperalgesia and reduces IL-10 production. We propose that low GRK2 expression and/or impaired IL-10 production by monocytes/macrophages represent peripheral biomarkers for the risk of developing chronic pain after inflammation.

Dataset Information

GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain.

Publications

GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain.

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