Figure 4:

Macrophages and resolution of pain. (A) Regulation of pain resolution via macrophage-nociceptor interactions. Macrophages express GPR37, a newly identified SPM receptor. Activation of macrophage GPR37 by NPD1 promotes phenotypic switch from M1-like macrophages to M2-like macrophages, which contribute to the resolution of inflammation and pain via increased release of IL-10 and TGF-β and decreased release of IL-1β and TNF. IL-10 and TGF-β can act on their respective receptors on nociceptors to inhibit peripheral sensitization [86, 87]. Activation of GPR37 also induces phagocytosis of pathogens (e.g., zymosan) and apoptotic neutrophils, which is a critical step for the resolution of inflammation and pain. IL-10 production in macrophages is also regulated by GRK2 [88], but the connection between GPR37 and GRK2 is still unknown. In addition, CGRP released from nociceptor neurons can regulate the anti-inflammatory function via its receptor complex CALCRL-RAMP1 on macrophages to enhance the expression of IL-10. CALCRL, calcitonin receptor-like receptor; NPD1, neuroprotectin D1; RAMP1, receptor activity-modifying protein 1; SPM, specialized pro-resolving mediator. Reproduced from Ref. [36] with permission. (B) Neuroprotectin D1/protectin D1 (NPD1/PD1), a SPM derived from DHA, induces phagocytosis of zymosan particles of peritoneal macrophages via GPR37. Note that NPD1-induced phagocytosis is diminished in macrophages from Gpr37 knockout mice. Reproduced from Chen et al. [36] with CCC permission.