GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain
Open Access
- 16 July 2018
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 128 (8), 3568-3582
- https://doi.org/10.1172/jci99888
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.Keywords
This publication has 56 references indexed in Scilit:
- Neurogenic inflammation and the peripheral nervous system in host defense and immunopathologyNature Neuroscience, 2012
- Infection regulates pro-resolving mediators that lower antibiotic requirementsNature, 2012
- Protective and pathogenic functions of macrophage subsetsNature Reviews Immunology, 2011
- Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actionsNature Medicine, 2010
- TRPV2 has a pivotal role in macrophage particle binding and phagocytosisNature Immunology, 2010
- Resolvin D1 binds human phagocytes with evidence for proresolving receptorsProceedings of the National Academy of Sciences of the United States of America, 2010
- Exploring the full spectrum of macrophage activationNature Reviews Immunology, 2008
- Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediatorsNature Reviews Immunology, 2008
- Resolvin E1 and protectin D1 activate inflammation-resolution programmesNature, 2007
- GPR37 associates with the dopamine transporter to modulate dopamine uptake and behavioral responses to dopaminergic drugsProceedings of the National Academy of Sciences of the United States of America, 2007