Accelerating the Reversal of Inflammatory Pain with NPD1 and Its Receptor GPR37

Accelerating the reversal of inflammatory pain with NPD1 and its receptor GPR37

Lintao Qu, Michael J. Caterina

J Clin Invest. 2018;128(8):3246-3249. https://doi.org/10.1172/JCI122203.

Commentary

Resolution of inflammation is a critical process that is facilitated by specialized proresolving mediators (SPMs). In this issue, Bang et al. show that the G protein–coupled receptor GPR37 is a receptor for one such SPM, neuroprotectin D1. They also show that GPR37 activation in macrophages enhances phagocytosis, shifts cytokine release toward an antiinflammatory profile, and thereby helps to reverse inflammatory pain.

Find the latest version: https://jci.me/122203/pdf COMMENTARY The Journal of Clinical Investigation Accelerating the reversal of inflammatory pain with NPD1 and its receptor GPR37

Lintao Qu1,2 and Michael J. Caterina1,2,3,4 1Department of Neurosurgery, 2Neurosurgery Pain Research Institute, 3Department of Biological Chemistry, and 4Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

NPD1, GPR37, and the resolution of inflammatory pain Resolution of inflammation is a critical process that is facilitated by GPR37 is a GPCR most extensively stud- specialized proresolving mediators (SPMs). In this issue, Bang et al. show ied in the brain that has been associ- that the G protein–coupled receptor GPR37 is a receptor for one such SPM, ated with Parkinson’s disease and autism neuroprotectin D1. They also show that GPR37 activation in macrophages spectrum disorder (14–16). Two known enhances phagocytosis, shifts cytokine release toward an antiinflammatory GPR37 ligands, prosaposin and prosaposin- profile, and thereby helps to reverse inflammatory pain. derived 14-mer peptide (TX14), have been shown to exert neuroprotective and glioprotective effects via this receptor (17). Prosaposin and TX14 have also Specialized proresolving lipids derived enzymatically from essen- been shown to alleviate tactile allodynia mediators as active tial fatty acids such as arachidonic acid in several models of neuropathic- and participants in resolution of (AA), eicosapentaenoic acid (EPA), and formalin-induced pain (17), although the inflammation docosahexaenoic acid (DHA) (4). Lipoxins relevant receptor for those actions was not The earliest events following tissue infec- (LXA4 and LXB4) are SPMs derived from identified. Moreover, the expression and tion or injury typically involve the sequen- AA (1, 5). Additional SPM families, includ- function of GPR37 in immune cells has tial recruitment of neutrophils and mac- ing resolvins, protectins, and maresins, not been previously addressed. To explore rophages, together with cardinal features were first identified by Serhan (2). E-series potential roles for GPR37 in inflammatory of inflammation: tumor (edema), calor resolvins (RvE1 and RvE2) are derived from pain, Bang et al. characterized the cellular (warmth), dolor (pain), rubor (redness), EPA whereas D-series resolvins (RvD1-6), distribution of GPR37 in mouse hind paw and functio laesa (loss of function). Over neuroprotectins/protectins (NPD1/PD1), skin, dorsal root ganglia (DRG, which time, however, antiinflammatory pro- and maresins are derived from DHA (refs. house sensory neuron cell bodies), the spi- cesses reduce immune cell infiltration by 6–8 and Figure 1A). As a class, SPMs share nal cord, and the brain (13). They detected reciprocally suppressing the release of pro- similar biological functions, including lim- GPR37 expression in a subset of macro- inflammatory cytokines while enhancing iting neutrophil infiltration, shifting cyto- phages in skin, peritoneal fluid, and DRG. the release of antiinflammatory cytokines. kine profiles from pro- to antiinflammatory, Interestingly, however, they observed no Meanwhile, proresolution processes limit and promoting macrophage phagocytosis. GPR37 in spinal or brain microglia, which further damage and enhance restoration of However, SPMs display cell-type–specific share many features with macrophages, or tissue homeostasis by promoting neutro- actions owing to differential expression of in peripheral sensory neurons. phil apoptosis and the phagocytic removal their receptors. SPMs exert most of their Bang et al. also provide several lines of of apoptotic neutrophils, cell debris, and effects via GPCRs such as those that bind evidence suggesting that GPR37 is a recep- residual pathogens by phagocytic mac- LXA4 (ALXR/FPR2) (9), RvE1 (chemokine- tor for NPD1 (13). First, NPD1, like prosa- rophages (1). These events coincide with like receptor 1/CHEMR23) (10), RvD1 posin and TX14, evoked Ca2+ responses reversal of inflammation and pain. Yet, (GPR32) (11), and RvD2 (GPR18) (12). Until in HEK293 cells transfected with GPR37 while mechanisms whereby proinflamma- now, however, the receptor that mediates the but not in those transfected with other tory mediators drive inflammatory pain proresolving actions of NPD1 has remained SPM receptors. Second, among multiple have been well-studied, relatively less is undefined. In this issue, Bang et al. identify SPMs screened, only NPD1 could activate known at the molecular level about how GPR37 (parkin-associated endothelin-like Ca2+ responses in GPR37-transfected cells. inflammatory pain is resolved. receptor/Pael-R) as a receptor for NPD1 and Third, genetic knockout of GPR37 abol- An array of specialized proresolving provide evidence implicating GPR37 as a ished NPD1-evoked Ca2+ responses in mediators (SPMs) (2, 3) generated endog- new molecular participant in macrophage cultured primary peritoneal macrophages. enously during inflammation promotes the phagocytosis and the resolution of inflam- And fourth, dot-blot assays supported the resolution of inflammation. Most SPMs are matory pain (13). ability of NPD1 to bind GPR37. Another important finding of Bang Related Article: p. 3568 et al. was that NPD1 could enhance macrophage phagocytosis of yeast-derived Conflict of interest: The authors have declared that no conflict of interest exists. zymosan particles, an effect that was absent Reference information: J Clin Invest. 2018;128(8):3246–3249. https://doi.org/10.1172/JCI122203. in peritoneal macrophages isolated from

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Figure 1. NPD1-GPR37 signaling promotes resolution of inflammatory pain. (A) Biosynthesis of neuroprotectin D1 (NPD1) from dietary docosahexaenoic acid (DHA). (B) Genetic knockout of the NPD1 receptor GPR37 prolongs pain evoked by zymosan injection without altering kinetics of immune cell trafficking or resolution of edema. (C) NPD1 and GPR37 signaling likely promotes resolution of inflammatory pain by both enhancing macrophage phagocytosis and shifting cytokine release toward an antiinflammatory profile. Onset of inflammation is at left; resolution phase is at right.

GPR37-KO mice (13). Using pharmacologi- determine the contributions of GPR37 and an M1-like macrophage phenotype. In cal inhibitors, they further determined that macrophages to the resolution of inflam- behavioral assays, naive GPR37-KO mice the potentiation of macrophage phagocy- matory pain (ref. 13 and Figure 1B). They showed normal withdrawal responses to tosis by NPD1 and GPR37 depends on sig- observed that GPR37-KO impaired in vivo painful mechanical, thermal, and chemical naling through G protein subunit Gi/o, ERK, macrophage phagocytosis of zymosan and stimuli. The onset and peak severity of and PI3K/AKT. This differs from RvD2/ apoptotic neutrophils but had no effect on mechanical and thermal hyperalgesia DRV2 signaling, which has been shown to neutrophil recruitment or on the reduction evoked by injection with zymosan were promote resolution via a pathway involving in neutrophil numbers at later time points also normal in GPR37-KO mice. However, cAMP, pCREB, STAT3, and ERK (18). (presumably a consequence of neutrophil despite a normal resolution of edema, Upon injection into rodent skin, apoptosis). In addition, GPR37 deficiency the resolution of inflammatory pain was zymosan particles evoke inflammation augmented the expression of proinflam- much slower in mice lacking GPR37 com- and associated mechanical and thermal matory cytokines (e.g., IL-1β) and recip- pared with WT controls, with substantial hypersensitivity that peak within approxi- rocally suppressed the expression of anti- residual hyperalgesia at 4 weeks. A simi- mately 4 hours but then revert back to inflammatory cytokines (e.g., IL-10 and lar pattern of normal onset of hyperalge- baseline within about one week. Bang TGF-β) in macrophages, suggesting that sia but delayed resolution was observed and colleagues employed this model to GPR37 activation favors an M2-like over in GPR37-KO mice injected with IL-1β.

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Thus, it appears that GPR37 plays a selec- in pain resolution is well-supported by Address correspondence to: Michael J. tive role in the resolution phase of inflam- the study of Bang et al. (13). However, any Caterina, 725 North Wolfe Street, Bal- matory pain, potentially by facilitating benefits of this receptor’s prophagocytic timore, Maryland 21205, USA. Phone: macrophage participation in proresolution effects, while conceptually reasonable, 410.502.5457; Email: [email protected]. events (summarized in Figure 1C). remain speculative. Although Bang et al. Bang et al. employed both gain- and show that the proportion of macrophage- 1. Serhan CN. Resolution phase of inflammation: loss-of-function approaches to further test engulfed neutrophils during the resolution novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu Rev this possibility (13). First, depletion of mac- phase of zymosan inflammation is depen- Immunol. 2007;25:101–137. rophages from WT mice using the chemi- dent on the presence of GPR37, knockout 2. Serhan CN. Pro-resolving lipid mediators cal toxin clodronate phenocopied the pro- of this receptor apparently does not alter are leads for resolution physiology. Nature. longed zymosan-induced pain phenotype either the recruitment of neutrophils to 2014;510(7503):92–101. seen in GPR37-KO mice. Second, and even zymosan-treated skin or the degree of 3. Serhan CN, Dalli J, Colas RA, Winkler JW, Chiang N. Protectins and maresins: new pro-resolving more strikingly, adoptive transfer of WT neutrophil elimination by day 5. While the families of mediators in acute inflammation and but not GPR37-deficient macrophages latter might be attributable, in part, to nor- resolution bioactive metabolome. Biochim Biophys into GPR37-KO mice reversed their pro- mal neutrophil apoptosis in the absence of Acta. 2015;1851(4):397–413. longed hyperalgesia phenotype. Moreover, GPR37, the specific respective contributions 4. Basil MC, Levy BD. Specialized pro-resolving the proresolving effect of adoptively trans- of neutrophil apoptosis and macrophage- mediators: endogenous regulators of infection and inflammation. Nat Rev Immunol. 2016;16(1):51–67. ferred WT macrophages was attenuated mediated phagocytosis to pain resolution 5. Petasis NA, et al. Design, synthesis and bioac- by neutralizing antibodies against IL-10. remain to be clarified. The precise inter- tions of novel stable mimetics of lipoxins and Taken together, these findings suggest that play between phagocytosis, inflammation, aspirin-triggered lipoxins. Prostaglandins Leukot GPR37 in macrophages promotes the reso- nociceptive neurons, and pain is likely to be Essent Fatty Acids. 2005;73(3-4):301–321. lution of inflammatory pain, at least in part especially relevant in the setting of infec- 6. Arita M, et al. Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentae- by promoting the release of IL-10. tion with living microorganisms. Recent noic acid, protects against 2,4,6-trinitrobenzene studies have shown that certain pathologi- sulfonic acid-induced colitis. Proc Natl Acad Sci Implications and future cal bacteria directly activate nociceptive U S A. 2005;102(21):7671–7676. directions neurons through the production of toxins 7. Serhan CN, et al. Anti-inflammatory actions of The findings of Bang et al. identify roles such as Streptolysin S, and that the conse- neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihydroxy- for a previously unappreciated ligand- quent release of neuropeptides from the containing docosatrienes. J Immunol. receptor pair in the resolution of inflam- nociceptive neurons suppresses recruit- 2006;176(3):1848–1859. matory pain. They also raise a number of ment of innate immune cells that would 8. Sun YP, et al. Resolvin D1 and its aspirin- important questions. First, what endog- normally phagocytose the bacteria to clear triggered 17R epimer. Stereochemical assign- enous ligand(s) drive GPR37-mediated or limit the infection (20). Presumably, ments, anti-inflammatory properties, and enzymatic inactivation. J Biol Chem. proresolution effects in the setting of mechanisms that augment phagocytosis, 2007;282(13):9323–9334. zymosan-induced pain? Are these events per se, would reduce bacterial growth and 9. Dufton N, Perretti M. Therapeutic anti- mediated by NPD1, prosaposin, TX14, or consequently pain in this setting. However, inflammatory potential of formyl-peptide receptor other, unidentified GPR37 ligands? Time- this idea remains to be directly tested. agonists. Pharmacol Ther. 2010;127(2):175–188. resolved biochemical assays for SPMs Fourth, in the setting of peripheral 10. Arita M, et al. Stereochemical assignment, antiinflammatory properties, and receptor for the during zymosan inflammation, coupled nerve injury, do GPR37 or other SPMs omega-3 lipid mediator resolvin E1. J Exp Med. with selective blockade of their synthesis, facilitate macrophage phagocytosis of 2005;201(5):713–722. could help to address this issue. axonal and myelin debris and is this effect 11. Krishnamoorthy S, et al. Resolvin D1 binds Second, what might be the utility of dif- a contributing factor to effective nerve human phagocytes with evidence for prore- ferent SPMs engaging different signaling regeneration and subsequent reversal of solving receptors. Proc Natl Acad Sci U S A. 2010;107(4):1660–1665. pathways (G /Ca2+/PI3K/ERK vs. cAMP/ neuropathic pain? i/o 12. Chiang N, Dalli J, Colas RA, Serhan CN. pCREB/STAT3/ERK) to promote phago- Collectively, the findings of Bang et al. Identification of resolvin D2 receptor mediating cytosis by innate immune cells? Do these (13) identify new molecular participants resolution of infections and organ protection. pathways act additively or synergistically, (and attractive candidate therapeutic tar- J Exp Med. 2015;212(8):1203–1217. or function complementarily to target gets) in the resolution of inflammatory 13. Bang S, Xie YK, Zhang ZJ, Wang Z, Xu ZZ, Ji RR. GPR37 regulates macrophage phagocytosis and different cellular populations or preferential- pain, highlight the utility of the zymosan resolution of inflammatory pain. J Clin Invest. ly enhance the phagocytosis of distinct sub- system for the analysis of “active” reso- 2018;128(8):3568–3582. strates? Furthermore, do these events occur lution of pain, and bring into focus new 14. Fujita-Jimbo E, et al. Mutation in Parkinson in parallel with the reported direct analgesic questions about the details of this multi- disease-associated, G-protein-coupled receptor effects of SPMs on sensory neurons (19)? faceted process. 37 (GPR37/PaelR) is related to autism spectrum disorder. PLoS One. 2012;7(12):e51155. Third, what is the relative importance 15. Marazziti D, Gallo A, Golini E, Matteoni R, of GPR37-augmented phagocytosis vs. Acknowledgments Tocchini-Valentini GP. Molecular cloning and cytokine profile shift to the resolution of Supported by the Neurosurgery Pain chromosomal localization of the mouse Gpr37 inflammatory pain? A major role for GPR37- Research Institute at Johns Hopkins and gene encoding an orphan G-protein-coupled stimulated macrophage IL-10 secretion by NIH R01AR072230 to LQ. peptide receptor expressed in brain and testis.

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Genomics. 1998;53(3):315–324. dynia. Pain. 2006;121(1–2):14–21. subtype V1/A1, inflammatory pain, and spi- 16. Murakami T, et al. Pael-R is accumulated in 18. Chiang N, de la Rosa X, Libreros S, Serhan CN. nal cord synaptic plasticity in mice: distinct Lewy bodies of Parkinson’s disease. Ann Neurol. Novel resolvin D2 receptor axis in infectious roles of resolvin D1, D2, and E1. J Neurosci. 2004;55(3):439–442. inflammation. J Immunol. 2017;198(2):842–851. 2011;31(50):18433–18438. 17. Jolivalt CG, Ramos KM, Herbetsson K, Esch FS, 19. Park CK, Xu ZZ, Liu T, Lü N, Serhan CN, 20. Pinho-Ribeiro FA, et al. Blocking neuronal signal- Calcutt NA. Therapeutic efficacy of prosaposin- Ji RR. Resolvin D2 is a potent endogenous ing to immune cells treats streptococcal invasive derived peptide on different models of allo- inhibitor for transient receptor potential infection. Cell. 2018;173(5):1083–1097.e22.

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