Resolution of Inflammatory Pain by Endogenous Chemerin and G Protein-Coupled Receptor ChemR23.
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ABSTRACT:
SUBMITTER: Xie YK
PROVIDER: S-EPMC8423872 | biostudies-literature | 2021 Sep
REPOSITORIES: biostudies-literature
Publications
Resolution of Inflammatory Pain by Endogenous Chemerin and G Protein-Coupled Receptor ChemR23.
Xie Ya-Kai YK Luo Hao H Qiu Xiao-Yun XY Xu Zhen-Zhong ZZ
Neuroscience bulletin 20210527 9
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Project description:Chemerin is a chemotactic protein that binds to the G protein-coupled receptor, ChemR23. We demonstrate that murine chemerin possesses potent antiinflammatory properties that are absolutely dependent on proteolytic processing. A series of peptides was designed, and only those identical to specific C-terminal chemerin sequences exerted antiinflammatory effects at picomolar concentrations in vitro. One of these, chemerin15 (C15; A(140)-A(154)), inhibited macrophage (MPhi) activation to a similar extent as proteolyzed chemerin, but exhibited reduced activity as a MPhi chemoattractant. Intraperitoneal administration of C15 (0.32 ng/kg) to mice before zymosan challenge conferred significant protection against zymosan-induced peritonitis, suppressing neutrophil (63%) and monocyte (62%) recruitment with a concomitant reduction in proinflammatory mediator expression. Importantly, C15 was unable to ameliorate zymosan-induced peritonitis in ChemR23(-/-) mice, demonstrating that C15's antiinflammatory effects are entirely ChemR23 dependent. In addition, administration of neutralizing anti-chemerin antibody before zymosan challenge resulted in a significant exacerbation of peritoneal inflammation (up to 170%), suggesting an important endogenous antiinflammatory role for chemerin-derived species. Collectively, these results show that chemerin-derived peptides may represent a novel therapeutic strategy for the treatment of inflammatory diseases through ChemR23.
| S-EPMC2292217 | biostudies-literature
Project description:Macrophages constitute a major component of innate immunity and play an essential role in defense mechanisms against external aggressions and in inflammatory responses. Chemerin, a chemoattractant protein, is generated in inflammatory conditions, and recruits cells expressing the G protein-coupled receptor ChemR23, including macrophages. Chemerin was initially expected to behave as a pro-inflammatory agent. However, recent data described more complex activities that are either pro- or anti-inflammatory, according to the disease model investigated. In the present study, peritoneal macrophages were generated from WT or ChemR23(-/-) mice, stimulated with lipopolyssaccharide in combination or not with IFN-? and the production of pro- (TNF-?, IL-1? and IL-6) and anti-inflammatory (IL-10) cytokines was evaluated using qRT-PCR and ELISA. Human macrophages generated from peripheral blood monocytes were also tested in parallel. Peritoneal macrophages from WT mice, recruited by thioglycolate or polyacrylamide beads, functionally expressed ChemR23, as assessed by flow cytometry, binding and chemotaxis assays. However, chemerin had no effect on the strong upregulation of cytokine release by these cells upon stimulation by LPS or LPS/IFN-?, whatever the concentration tested. Similar data were obtained with human macrophages. In conclusion, our results rule out the direct anti-inflammatory effect of chemerin on macrophages ex vivo, described previously in the literature, despite the expression of a functional ChemR23 receptor in these cells.
| S-EPMC3386906 | biostudies-literature
Project description:Chemerin peptides represent a recently identified component of the endogenous anti-inflammatory network that act via the G protein-coupled receptor ChemR23. The role of the chemerin peptide/ChemR23 pathway in phagocytosis, the clearance of apoptotic cells (efferocytosis), and the resolution of inflammation is unknown. In this article, we report that low picomolar concentrations of the chemerin peptide chemerin15 (C15) enhance macrophage (MPhi) phagocytosis of microbial particles and apoptotic cells by up to 360% in vitro. These prophagocytic effects of C15 are significantly impaired in ChemR23(-/-) MPhis and are associated with increased actin polymerization and localization of F-actin to the phagocytic cup. Importantly, pharmacological inhibition of Syk activity completely abrogates the prophagocytic activities of C15 and associated changes in actin polymerization and phagocytic cup formation, suggesting that C15 promotes phagocytosis by facilitating phagocytic cup development in a Syk-dependent manner. During peritoneal inflammation, C15 administration (8 pg/mouse) enhances microbial particle clearance and apoptotic neutrophil ingestion by MPhis in wild-type but not ChemR23(-/-) mice, such that levels of apoptotic and necrotic cells at the inflammatory site are profoundly reduced. In contrast, neutralization of endogenous chemerin species during peritoneal inflammation significantly impairs MPhi ingestion of apoptotic neutrophils and zymosan. Our data identify a key role of the chemerin peptide/ChemR23 axis in the efficient clearance of foreign material, efferocytosis, and, hence, the resolution of inflammation. Manipulation of the chemerin peptide/ChemR23 axis may represent a novel therapeutic approach for the treatment of inflammatory pathologies, especially if failure to efficiently clear phagocytic targets has been implicated in their pathogenesis.
| S-EPMC4237835 | biostudies-literature
Project description:Chemerin receptor (CMKLR1) is a G protein-coupled receptor (GPCR) implicated in macrophage-mediated inflammation and in several forms of human arthritis. Analogous to other GPCR, CMKLR1 is likely regulated by G protein-coupled receptor kinase (GRK) phosphorylation of intracellular domains in an activation-dependent manner, which leads to recruitment and termination of intracellular signaling via desensitization and internalization of the receptor. The ubiquitously expressed GRK family members include GRK2, GRK3, GRK5, and GRK6, but it is unknown which GRK regulates CMKLR1 cellular and signaling functions. Our data show that activation of CMKLR1 by chemerin in primary macrophages leads to signaling and functional outcomes that are regulated by GRK6 and β-arrestin 2. We show that arrestin recruitment to CMKLR1 following chemerin stimulation is enhanced with co-expression of GRK6. Further, internalization of endogenous CMKLR1, following the addition of chemerin, is decreased in inflammatory macrophages from GRK6- and β-arrestin 2-deficient mice. These GRK6- and β-arrestin 2-deficient macrophages display increased migration toward chemerin and altered AKT and Extracellular-signal Related Kinase (ERK) signaling. Our findings show that chemerin-activated CMKLR1 regulation in inflammatory macrophages is largely GRK6 and β-arrestin mediated, which may impact innate immunity and have therapeutic implications in rheumatic disease.
| S-EPMC6584946 | biostudies-literature
Project description:G protein-coupled receptors (GPCRs) are membrane proteins that play important roles in biology. However, our understanding of their function in complex living systems is limited because we lack tools that can target individual receptors with sufficient precision. State-of-the-art approaches, including DREADDs, optoXRs, and PORTL gated-receptors, control GPCR signaling with molecular, cell type, and temporal specificity. Nonetheless, these tools are based on engineered non-native proteins that may (i) express at nonphysiological levels, (ii) localize and turnover incorrectly, and/or (iii) fail to interact with endogenous partners. Alternatively, membrane-anchored ligands (t-toxins, DARTs) target endogenous receptors with molecular and cell type specificity but cannot be turned on and off. In this study, we used a combination of chemistry, biology, and light to control endogenous metabotropic glutamate receptor 2 (mGluR2), a Family C GPCR, in primary cortical neurons. mGluR2 was rapidly, reversibly, and selectively activated with photoswitchable glutamate tethered to a genetically targeted-plasma membrane anchor (membrane anchored Photoswitchable Orthogonal Remotely Tethered Ligand; maPORTL). Photoactivation was tuned by adjusting the length of the PORTL as well as the expression level and geometry of the membrane anchor. Our findings provide a template for controlling endogenous GPCRs with cell type specificity and high spatiotemporal precision.
| S-EPMC7271769 | biostudies-literature
Project description:Chemokine-like receptor 1 (CMKLR1), also known as chemerin receptor 23 (ChemR23) or chemerin receptor 1, is a chemoattractant G protein-coupled receptor (GPCR) that responds to the adipokine chemerin and is highly expressed in innate immune cells, including macrophages and neutrophils. The signaling pathways of CMKLR1 can lead to both pro- and anti-inflammatory effects depending on the ligands and physiological contexts. To understand the molecular mechanisms of CMKLR1 signaling, we determined a high-resolution cryo-electron microscopy (cryo-EM) structure of the CMKLR1-Gi signaling complex with chemerin9, a nanopeptide agonist derived from chemerin, which induced complex phenotypic changes of macrophages in our assays. The cryo-EM structure, together with molecular dynamics simulations and mutagenesis studies, revealed the molecular basis of CMKLR1 signaling by elucidating the interactions at the ligand-binding pocket and the agonist-induced conformational changes. Our results are expected to facilitate the development of small molecule CMKLR1 agonists that mimic the action of chemerin9 to promote the resolution of inflammation.
| S-EPMC10699647 | biostudies-literature
Project description: Not available
| S-EPMC7132303 | biostudies-literature
Project description:Receptor component protein (RCP) is a 148 amino acid intracellular peripheral membrane protein, previously identified as promoting the coupling of CGRP to cAMP production at the CGRP receptor, a heterodimer of calcitonin receptor like-receptor (CLR), a family B G protein-coupled receptor (GPCR) and receptor activity modifying protein 1 (RAMP1). We extend these observations to show that it selectively enhances CGRP receptor coupling to Gs but not Gq or pERK activation. At other family B GPCRs, it enhances cAMP production at the calcitonin, corticotrophin releasing factor type 1a and glucagon-like peptide type 2 receptors with their cognate ligands but not at the adrenomedullin type 1 (AM1), gastric inhibitory peptide and glucagon-like peptide type 1 receptors, all expressed in transfected HEK293S cells. However, there is also cell-line variability as RCP did not enhance cAMP production at the endogenous calcitonin receptor in HEK293T cells and it has previously been reported that it is active on the AM1 receptor expressed on NIH3T3 cells. RCP appears to behave as a positive allosteric modulator at coupling a number of family B GPCRs to Gs, albeit in a manner that is regulated by cell-specific factors. It may exert its effects at the interface between the 2nd intracellular loop of the GPCR and Gs, although there is likely to be some overlap between this location and that occupied by the C-terminus of RAMPs if they bind to the GPCRs.
| S-EPMC6977087 | biostudies-literature
Project description:BackgroundChemerin is an adipokine that signals through the G protein-coupled receptor ChemR23 and is associated with inflammation, glucose homeostasis, lipid metabolism and renal function, all of which strongly influence cardiovascular risk. However, elevated chemerin provides a survival advantage in patients with chronic kidney disease (CKD), but how this relates to the cardiovascular phenotype is unknown.ObjectivesThe aim of the present study was to establish the association of chemerin with coronary calcification and to determine the effects of chemerin signalling, through ChemR23, in vascular smooth muscle cell (VSMC) calcification.MethodsPlasma chemerin was measured in 113 patients with CKD and 50 healthy controls. All patients underwent computed tomography to determine coronary artery calcium (CAC) score. VSMCs were isolated from wild-type and ChemR23 knock-out mice and treated with chemerin.ResultsMultivariate analyses established creatinine, cholesterol, body mass index and tumour necrosis factor as significant confounders for circulating chemerin levels. Despite these positive associations with renal function, cardiometabolic risk factors and inflammation, chemerin was inversely associated with CAC both in an age- and sex-adjusted analysis and in a multivariate analysis adjusting for the aforementioned confounders. In addition, circulating chemerin levels were associated with the calcification inhibitors matrix gla protein (MGP) and fetuin-A. Finally, chemerin significantly reduced phosphate-induced calcification and increased MGP expression in VSMCs, whereas chemerin was devoid of these effects in VSMCs lacking ChemR23.ConclusionIn conclusion, these results suggest that chemerin signalling through ChemR23 in VSMCs protects against vascular calcification in CKD.
| S-EPMC6852438 | biostudies-literature
Project description:BACKGROUND: Chronic inflammatory pain, when not effectively treated, is a costly health problem and has a harmful effect on all aspects of health-related quality of life. Despite the availability of pharmacologic treatments, chronic inflammatory pain remains inadequately treated. Understanding the nociceptive signaling pathways of such pain is therefore important in developing long-acting treatments with limited side effects. High local proton concentrations (tissue acidosis) causing direct excitation or modulation of nociceptive sensory neurons by proton-sensing receptors are responsible for pain in some inflammatory pain conditions. We previously found that all four proton-sensing G-protein-coupled receptors (GPCRs) are expressed in pain-relevant loci (dorsal root ganglia, DRG), which suggests their possible involvement in nociception, but their functions in pain remain unclear. RESULTS: In this study, we first demonstrated differential change in expression of proton-sensing GPCRs in peripheral inflammation induced by the inflammatory agents capsaicin, carrageenan, and complete Freund's adjuvant (CFA). In particular, the expression of TDAG8, one proton-sensing GPCR, was increased 24 hours after CFA injection because of increased number of DRG neurons expressing TDAG8. The number of DRG neurons expressing both TDAG8 and transient receptor potential vanilloid 1 (TRPV1) was increased as well. Further studies revealed that TDAG8 activation sensitized the TRPV1 response to capsaicin, suggesting that TDAG8 could be involved in CFA-induced chronic inflammatory pain through regulation of TRPV1 function. CONCLUSION: Each subtype of the OGR1 family was expressed differently, which may reflect differences between models in duration and magnitude of hyperalgesia. Given that TDAG8 and TRPV1 expression increased after CFA-induced inflammation and that TDAG8 activation can lead to TRPV1 sensitization, it suggests that high concentrations of protons after inflammation may not only directly activate proton-sensing ion channels (such as TRPV1) to cause pain but also act on proton-sensing GPCRs to regulate the development of hyperalgesia.
| S-EPMC2716309 | biostudies-literature