CCL2 and CCL3 are essential mediators of pelvic pain in experimental autoimmune prostatitis

Quick, Marsha L.; Mukherjee, Soumi; Rudick, Charles N.; Done, Joseph D.; Schaeffer, Anthony J.; Thumbikat, Praveen

doi:10.1152/ajpregu.00240.2012

Cited by 69 publications

(90 citation statements)

References 35 publications

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“…Our results showing almost complete prevention of UPK3A 65-84-induced tactile allodynia by genetic deletion of either CCL2 or its receptor CCR2 are similar to the findings of Quick et al (44) in C57BL/6J mice with experimental autoimmune prostatitis, suggesting a common mechanism in bladder-generated and prostate-generated pelvic allodynia. Furthermore, we showed that accumulations of activated, resting, and total Ϫ/Ϫ mice and Ccr2 Ϫ/Ϫ mice immunized with UPK3A 65-84.…”

Section: Discussionsupporting

confidence: 91%

“…A remaining question is whether the primary effects of Ccl2 and Ccr2 gene deletions in this EAC model were in mast cell recruitment and allodynia or in the initial immune response to UPK3A 65-84 immunization. In the experimental autoimmune prostatitis model of Quick et al (44), male Ccr2 Ϫ/Ϫ mice immunized with rat prostate lysate were completely protected from pelvic allodynia and exhibited only small, nonsignificant reductions in numbers of prostate-infiltrating CD4-positive and CD8-positive T cells compared with WT mice. In separate studies (21,25) of myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis, Ccl2 Ϫ/Ϫ mice and Ccr2 Ϫ/Ϫ mice on the C57BL/6 background exhibited less motor impairment than WT mice, but adoptive transfer of antigen primed T cells from the knockout mice to naïve WT recipients induced the disease phenotype.…”

Section: Discussionmentioning

confidence: 94%

“…Also, mice with genetic deletion of chemokine (C-C motif) receptor 2 (CCR2), the receptor on the surface of mast cells for CCL2 and other chemokines, exhibited reduced tactile pain responses after nerve injury (1). More recently, C57BL/6J mice with genetic deletion of either Ccl2 or Ccr2 were shown to be resistant to pelvic hyperalgesia associated with experimental autoimmune prostatitis (44). Increased levels of CCL2 have been found in urine and bladder tissue of IC/PBS patients (39), and CCL2 has been suggested as a biomarker for IC/PBS and chronic pelvic pain syndrome (17,39).…”

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confidence: 99%

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Chronic pelvic allodynia is mediated by CCL2 through mast cells in an experimental autoimmune cystitis model

Bicer

Altuntas

İzgi

et al. 2015

American Journal of Physiology-Renal Physiology

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 99%

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Chronic pelvic allodynia is mediated by CCL2 through mast cells in an experimental autoimmune cystitis model

Bicer

Altuntas

İzgi

et al. 2015

American Journal of Physiology-Renal Physiology

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“…Chemokine secretion has been evaluated in both semen and expressed prostatic secretion from men with prostatitis showing that CXCL5 and CXCL8 were elevated in expressed prostatic secretion from men with bacterial prostatitis, CPPS, and asymptomatic inflammatory prostatitis (10,44), chemokines that are both highly angiogenic and leukoattractant. In addition, CCL2 and CCL3 have also been postulated as biomarkers correlating with pelvic pain symptoms (45,46). However, the expression of CXCR3 or CCR6 ligands in prostate tissue from patients bearing CCPS has not been investigated to date.…”

Section: Discussionmentioning

confidence: 99%

Expression of CXCR3 on Specific T Cells Is Essential for Homing to the Prostate Gland in an Experimental Model of Chronic Prostatitis/Chronic Pelvic Pain Syndrome

Breser

Motrich

Sánchez

et al. 2013

The Journal of Immunology

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Experimental autoimmune prostatitis (EAP) is considered a valid model for the human disease chronic prostatitis/chronic pelvic pain syndrome. In this report, we analyzed phenotypic characteristics of T cells that gain access to the prostate and induce leukocyte recruitment in mice with different susceptibility to EAP. After EAP induction, NOD mice developed a specific cellular response characterized by a mixed Th1/Th17 pattern with specific T cells mainly expressing CXCR3 that infiltrated and damaged the prostate. In contrast, BALB/c mice, as well as NOD-IFN-γ−/−, exhibited only Th17 cells mainly expressing CCR6 that were not capable of infiltrating the prostate gland. Adoptive transfer experiments of T cells from NOD or NOD–IFN-γ−/− mice to NOD-SCID recipients showed that only T cells from NOD mice successfully infiltrated the prostate. However, after “in vitro” or “in vivo” treatment with rIFN-γ, T cells from NOD–IFN-γ−/− mice became capable of homing to the prostate and induced leukocyte recruitment. Chemokine levels in prostate tissue from NOD mice showed increased expression levels of CXCR3 ligands. Additional experiments using adoptive transfer of sorted CXCR3+CD3+ T cells or administrating a CXCR3 antagonist treatment confirmed these previous results. Altogether, our results demonstrate that the expression of CXCR3 on effector T cells is essential for their homing to the prostate gland in EAP. CXCR3 emerges as a potential therapeutic target to control chronic prostatitis/chronic pelvic pain syndrome.

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“…Mice were tested for pelvic pain by a blinded tester as previously described by our laboratory [37; 38; 40]. Briefly, mice were habituated for one hour by placing them in individual plexiglass chambers (6×10×12 cm) on top of a stainless steel wire grid floor and suspended 2 feet above a flat surface.…”

Section: Methodsmentioning

confidence: 99%

Tryptase-PAR2 axis in experimental autoimmune prostatitis, a model for chronic pelvic pain syndrome

Roman

Done

Schaeffer

et al. 2014

Pain

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Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) affects up to 15% of the male population and is characterized by pelvic pain. Mast cells are implicated in the murine experimental autoimmune prostatitis (EAP) model as key to chronic pelvic pain development. The mast cell mediator tryptase-β and its cognate receptor protease-activated receptor 2 (PAR2) are involved in mediating pain in other visceral disease models. Prostatic secretions and urines from CP/CPPS patients were examined for the presence of mast cell degranulation products. Tryptase-β and PAR2 expression were examined in murine experimental autoimmune prostatitis (EAP). Pelvic pain and inflammation were assessed in the presence or absence of PAR2 expression and upon PAR2 neutralization. Tryptase-β and carboxypeptidase A3 were elevated in CP/CPPS compared to healthy volunteers. Tryptase-β was capable of inducing pelvic pain and was increased in EAP along with its receptor PAR2. PAR2 was required for the development of chronic pelvic pain in EAP. PAR2 signaling in dorsal root ganglia lead to ERK1/2 phosphorylation and calcium influx. PAR2 neutralization using antibodies attenuated chronic pelvic pain in EAP. The tryptase-PAR2 axis is an important mediator of pelvic pain in EAP and may play a role in the pathogenesis of CP/CPPS.

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CCL2 and CCL3 are essential mediators of pelvic pain in experimental autoimmune prostatitis

Cited by 69 publications

References 35 publications

Chronic pelvic allodynia is mediated by CCL2 through mast cells in an experimental autoimmune cystitis model

Chronic pelvic allodynia is mediated by CCL2 through mast cells in an experimental autoimmune cystitis model

Expression of CXCR3 on Specific T Cells Is Essential for Homing to the Prostate Gland in an Experimental Model of Chronic Prostatitis/Chronic Pelvic Pain Syndrome

Tryptase-PAR2 axis in experimental autoimmune prostatitis, a model for chronic pelvic pain syndrome

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