title: Chronic pelvic allodynia is mediated by CCL2 through mast cells in an experimental autoimmune cystitis model.
abstract: The cause of chronic pelvic pain in interstitial cystitis/painful bladder syndrome (IC/PBS) remains unclear; autoimmunity is a possible etiology. We have recently shown that injection of a single immunogenic peptide of uroplakin 3A (UPK3A 65-84) induces experimental autoimmune cystitis (EAC) in female BALB/cJ mice that is unique among experimental models in accurately reflecting both the urinary symptoms and pelvic pain of IC/PBS. The aim of this project was to identify the roles of mast cells and mast cell chemoattractant/activator monocyte chemoattractant protein-1 [chemokine (C-C motif) ligand 2 (CCL2)] in the allodynia in this model. We immunized 6- to 8-wk-old female BALB/cJ mice with UPK3A 65-84 peptide and, 5-40 days later, observed increased responses to stimulation of the suprapubic abdominal and hindpaw surfaces with von Frey monofilaments compared with mice injected with adjuvant alone. Suprapubic and hindpaw tactile allodynia responses by EAC mice were blocked by instillation of lidocaine into the bladder but not by lidocaine in the uterus, confirming the bladder as the source of the hypersensitivity. Markedly increased numbers of activated mast cells and expression of CCL2 were found in the bladder after immunization with UPK3A 65-84. Hypersensitive responses were inhibited by mast cell stabilizer cromolyn sodium and antagonists of histamine receptors 1 and 2. Furthermore, BALB/cJ mice with deletion of the Ccl2 or chemokine (C-C motif) receptor 2 gene exhibited markedly reduced allodynia and accumulation of mast cells after UPK3A 65-84 immunization. These results show that UPK3A 65-84 immunization causes chronic visceral allodynia and suggest that it is mediated by CCL2-driven mast cell accumulation in the bladder.
authors.affiliation: Urology Institute, University Hospitals Case Medical Center and Department of Urology, Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Clinical Chemistry, Cleveland State University, Cleveland, Ohio;
authors.forename: Fuat
authors.initials: F
authors.lastname: Bicer
authors.affiliation: Urology Institute, University Hospitals Case Medical Center and Department of Urology, Case Western Reserve University School of Medicine, Cleveland, Ohio;
authors.forename: Cengiz Z
authors.initials: CZ
authors.lastname: Altuntas
authors.affiliation: Urology Institute, University Hospitals Case Medical Center and Department of Urology, Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Clinical Chemistry, Cleveland State University, Cleveland, Ohio;
authors.forename: Kenan
authors.initials: K
authors.lastname: Izgi
authors.affiliation: Urology Institute, University Hospitals Case Medical Center and Department of Urology, Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio; and.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Ozer
authors.affiliation: Urology Institute, University Hospitals Case Medical Center and Department of Urology, Case Western Reserve University School of Medicine, Cleveland, Ohio;
authors.forename: Michael
authors.initials: M
authors.lastname: Kavran
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Vincent K
authors.initials: VK
authors.lastname: Tuohy
authors.affiliation: Urology Institute, University Hospitals Case Medical Center and Department of Urology, Case Western Reserve University School of Medicine, Cleveland, Ohio; fxd22@case.edu.
authors.forename: Firouz
authors.initials: F
authors.lastname: Daneshgari
mesh_terms: D000818:Animals; D017332:Cetirizine; D018932:Chemokine CCL2 / Q000378:metabolism*; D004205:Cromolyn Sodium; D018856:Cystitis, Interstitial / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006636:Histamine Release; D006930:Hyperalgesia / Q000209:etiology* / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000502:physiology*; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011899:Ranitidine; D054390:Receptors, CCR2 / Q000378:metabolism; D001743:Urinary Bladder / Q000276:immunology / Q000378:metabolism; D060171:Uroplakin III / Q000276:immunology*
chemical_list: C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2; C554661:Upk3a protein, mouse; D060171:Uroplakin III; D011899:Ranitidine; D004205:Cromolyn Sodium; D017332:Cetirizine
keywords: chemokine (C-C motif) ligand 2-deficient mice; chemokine (C-C motif) receptor 2-deficient mice; mast cell inhibitors; pelvic pain; uroplakin 3A