GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain
Sangsu Bang, … , Zhen-Zhong Xu, Ru-Rong Ji
Sangsu Bang, … , Zhen-Zhong Xu, Ru-Rong Ji
Published July 16, 2018
Citation Information: J Clin Invest. 2018;128(8):3568-3582. https://doi.org/10.1172/JCI99888.
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Research Article Inflammation Neuroscience

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.

Authors

Sangsu Bang, Ya-Kai Xie, Zhi-Jun Zhang, Zilong Wang, Zhen-Zhong Xu, Ru-Rong Ji

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Figure 3

NPD1 enhances MΦ phagocytic activity in vitro via GPR37.

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NPD1 enhances MΦ phagocytic activity in vitro via GPR37. (A) NPD1 enhanc...
(A) NPD1 enhanced phagocytosis in WT pMΦs, as revealed by fluorescence-labeled zymosan particles. Note the reduction in NPD1-induced phagocytosis in Gpr37–/– mice. Scale bars: 10 μm. (B) Quantification of pMΦ phagocytic activity according to the number of zymosan particles (top) and percentage of cells (bottom) with phagocytic activity (>1 particle/cell). Note the dose-dependent phagocytic activity induced by NPD1. #P < 0.05 versus control (vehicle, PBS); *P < 0.05 versus Gpr37–/–; 2-way ANOVA followed by Bonferroni’s post hoc test. n = 4–5 cultures/group. (C) Phagocytic activity in pMΦs from WT and Gpr37–/– mice following treatment with RvD1 (100 nM), RvE1 (100 nM), TX14 (100 nM), and ionomycin (2 μM), as revealed by the number of zymosan particles (top) and percentage of cells with phagocytosis (bottom). #P < 0.05 versus vehicle; *P < 0.05 versus Gpr37–/–; 2-way ANOVA followed by Bonferroni’s post hoc test. n = 3–5 cultures/group. (D) Effects of LY294002 (50 μM), U0126 (10 μM), PTX (1 μg/ml), BAPTA-AM (10 μM), and ionomycin (2 μM) on basal and NPD1-induced (30 nM) phagocytosis. *P < 0.05 versus vehicle (with NPD1); #P < 0.05, NPD1 versus control; 2-way ANOVA followed by Bonferroni’s post hoc test. n = 3–5 cultures/group. For each culture, 113–503 cells were analyzed. Data represent the mean ± SEM.