Development of a Membrane-anchored Chemerin Receptor Agonist as a Novel Modulator of Allergic Airway Inflammation and Neuropathic Pain

Doyle, Jamie R.; Krishnaji, Subrahmanian Tarakkad; Zhu, Guangli; Xu, Zhen-Zhong; Heller, Daniel; Ji, Ru-Rong; Levy, Bruce D.; Kumar, Krishna; Kopin, Alan S.

doi:10.1074/jbc.m113.522680

Cited by 25 publications

(21 citation statements)

References 39 publications

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“…Despite the modest response toward HDM alone in our model, chemR23 KO mice were also more susceptible to (exclusively) HDM-induced allergic airway inflammation, with enhanced eosinophilia and T H 2 cytokine production compared with WT mice. Interestingly, in independent models of HDM-or OVA-induced airway inflammation, exogenously administered chemerin was reported to be associated with an anti-inflammatory response (18,22) suggesting that chemerin mediates its antiinflammatory properties in models of allergic airway inflammation by signaling via chemR23. The chemerin/chemR23 axis was also found to mediate anti-inflammatory responses in models of viral pneumonia and LPS-induced lung inflammation (16,17).…”

Section: Discussionmentioning

confidence: 99%

“…Given the anti-inflammatory role of the chemerin/chemR23 axis in diverse lung disease models, including models of allergic airway inflammation, chemerin or chemR23 agonists are proposed as novel candidate therapeutics for treatment of asthma (18,22). On the other hand, blocking chemR23 is also suggested as therapeutic intervention in disease models in which the chemR23 axis has proinflammatory properties (15).…”

Section: Discussionmentioning

confidence: 99%

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Pro- and Anti-Inflammatory Role of ChemR23 Signaling in Pollutant-Induced Inflammatory Lung Responses

Provoost

Grove

Fraser

et al. 2016

The Journal of Immunology

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Inhalation of traffic-related particulate matter (e.g., diesel exhaust particles [DEPs]) is associated with acute inflammatory responses in the lung, and it promotes the development and aggravation of allergic airway diseases. We previously demonstrated that exposure to DEP was associated with increased recruitment and maturation of monocytes and conventional dendritic cells (DCs), resulting in TH2 polarization. Monocytes and immature DCs express the G-protein coupled receptor chemR23, which binds the chemoattractant chemerin. Using chemR23 knockout (KO) and corresponding wild-type (WT) mice, we determined the role of chemR23 signaling in response to acute exposure to DEPs and in response to DEP-enhanced house dust mite (HDM)-induced allergic airway inflammation. Exposure to DEP alone, as well as combined exposure to DEP plus HDM, elevated the levels of chemerin in the bronchoalveolar lavage fluid of WT mice. In response to acute exposure to DEPs, monocytes and monocyte-derived DCs accumulated in the lungs of WT mice, but this response was significantly attenuated in chemR23 KO mice. Concomitant exposure to DEP plus HDM resulted in allergic airway inflammation with increased eosinophilia, goblet cell metaplasia, and TH2 cytokine production in WT mice, which was further enhanced in chemR23 KO mice. In conclusion, we demonstrated an opposing role for chemR23 signaling depending on the context of DEP-induced inflammation. The chemR23 axis showed proinflammatory properties in a model of DEP-induced acute lung inflammation, in contrast to anti-inflammatory effects in a model of DEP-enhanced allergic airway inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pro- and Anti-Inflammatory Role of ChemR23 Signaling in Pollutant-Induced Inflammatory Lung Responses

Provoost

Grove

Fraser

et al. 2016

The Journal of Immunology

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“…After completion of the desired peptide sequence, coupling of NFmoc-PEG8-propionic acid to the N terminus (g2-MSH) or the C terminus (BAM8-22) preceded coupling of the lipid (palmitic acid) using standard activation procedures (Doyle et al, 2014). Peptides were cleaved from the resin by using high hydrogen fluoride conditions (90% anhydrous hydrogen fluoride/10% anisole at 0°C for 1.5 hours), and precipitated using cold diethyl ether.…”

Section: Methodsmentioning

confidence: 99%

“…Conversely, type II MTLs result in an extracellular C terminus (Chou and Elrod, 1999;Harwood et al, 2013). Corresponding DNA templates were used from previously published tethered exendin (type I) and tethered chemerin (type II) constructs (Fortin et al, 2009;Doyle et al, 2014). DNA sequences corresponding to the peptide ligands were each sequentially replaced with those encoding BAM8-22 (VGRPEWWMDYQKRYG) and g2-MSH (YVMGHFRWDRFG) (Lembo et al, 2002) using oligonucleotidedirected site-specific mutagenesis, producing both type I and type II MTLs for each peptide (Fortin et al, 2009;Harwood et al, 2013).…”

Section: Methodsmentioning

confidence: 99%

“…Such membrane-tethered ligands (MTLs) provide a complementary tool to explore GPCR function (Fortin et al, 2011(Fortin et al, , 2009Harwood et al, 2013). Conversion of these recombinant ligands into synthetic membrane-anchored ligands (SMALs), in which a peptide is covalently coupled to a flexible linker and a lipid moiety, yields potent, soluble ligands that anchor to the cell surface and activate the corresponding GPCR ( Fortin et al, 2011;Doyle et al, 2014). The potential advantages of such ligands include increased potency and prolonged stability (Zhang and Bulaj, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Novel Probes Establish Mas-Related G Protein-Coupled Receptor X1 Variants as Receptors with Loss or Gain of Function

Heller

Doyle

Raman

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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The Mas-related G protein-coupled receptor X1 (MrgprX1) is a human seven transmembrane-domain protein with a putative role in nociception and pruritus. This receptor is expressed in dorsal root ganglion neurons and is activated by a variety of endogenous peptides, including bovine adrenal medulla peptide (BAM) and g2-melanocyte-stimulating hormone (g2-MSH). In the present work, we study how naturally occurring missense mutations alter the activity of MrgprX1. To characterize selected receptor variants, we initially used the endogenous peptide ligand BAM8-22. In addition, we generated and characterized a panel of novel recombinant and synthetic peptide ligands. Our studies identified a mutation in the second intracellular loop of MrgprX1, R131S, that causes a decrease in both ligandmediated and constitutive signaling. Another mutation in this region, H133R, results in a gain of function phenotype reflected by an increase in ligand-mediated signaling. Using epitope-tagged variants, we determined that the alterations in basal and ligand-mediated signaling were not explained by changes in receptor expression levels. Our results demonstrate that naturally occurring mutations can alter the pharmacology of MrgprX1. This study provides a theoretical basis for exploring whether MrgprX1 variability underlies differences in somatosensation within human populations.

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Chemerin/chemR23 axis in inflammation onset and resolution

2014

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Chemerin is an adipokine secreted by adipocytes and associated with obesity, insulin resistance and metabolic syndrome. Different chemerin fragments with pro- or anti-inflammatory action can be produced, depending on the class of proteases predominating in the microenvironment. Chemerin binds to three receptors, especially to chemR23, expressed on various cells, as dendritic cells, macrophages and natural killer cells, regulating chemotaxis towards the site of inflammation and activation status. Recently, the chemerin/chemR23 axis has attracted particular attention for the multiple roles related to the control of inflammation, metabolism and cancerogenesis in different organs and systems as lung (allergy and cancer), skin (psoriasis, lupus, cancer, wound repair), cardiovascular system (lipid profile and atherosclerosis), reproductive apparatus (polycystic ovary syndrome, follicular homoeostasis), and digestive tract (inflammatory bowel diseases and cancer). This pathway may regulate immune responses by contributing both to the pathogenesis of inflammatory diseases and to the resolution of acute inflammation. Thus, chemerin-derived peptides or other substances that may affect the chemerin/chemR23 axis could be used in the future for the treatment of many diseases, including cancer at different sites.

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Development of a Membrane-anchored Chemerin Receptor Agonist as a Novel Modulator of Allergic Airway Inflammation and Neuropathic Pain

Cited by 25 publications

References 39 publications

Pro- and Anti-Inflammatory Role of ChemR23 Signaling in Pollutant-Induced Inflammatory Lung Responses

Pro- and Anti-Inflammatory Role of ChemR23 Signaling in Pollutant-Induced Inflammatory Lung Responses

Novel Probes Establish Mas-Related G Protein-Coupled Receptor X1 Variants as Receptors with Loss or Gain of Function

Chemerin/chemR23 axis in inflammation onset and resolution

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