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 (MΦs) but not microglia, contributes to the resolution of inflammatory pain. Neuroprotectin D1 (NP...

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Bibliographic Details
Published in:The Journal of clinical investigation 2018-08, Vol.128 (8), p.3568-3582
Main Authors: Bang, Sangsu, Xie, Ya-Kai, Zhang, Zhi-Jun, Wang, Zilong, Xu, Zhen-Zhong, Ji, Ru-Rong
Format: Article
Language:English
Subjects:
Adoptive transfer
Alzheimer's disease
Autism
Biomedical research
Calcium (intracellular)
Calcium signalling
Cytokines
Dopamine
Flow cytometry
G proteins
Gene expression
Inflammation
Leukocytes (neutrophilic)
Macrophages
Microglia
Nerve tissue proteins
Neurons
Neutrophils
Pain
Parkinson's disease
Peritoneum
pH effects
Phagocytes
Phagocytosis
Rodents
Spinal cord
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI99888