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.

Evidence for the Role of Mast Cells in Cystitis-Associated Lower Urinary Tract Dysfunction: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Animal Model Study

“…Clinical trials in IC/BPS using mast cell inhibitors have been conducted and demonstrated to be promising [4–6]. In line with human studies, animal studies have demonstrated that mast cells are responsible for bladder inflammation and pain in diverse models [7–10]. However, despite these studies, the role of mast cells in cystitis-associated LUTD has not been identified.…”

“…Animal models with bladder autoimmune inflammation have been actively used in IC/BPS research for over two decades [10,19–24]. Experimental autoimmune cystitis (EAC) can be induced through immunization with bladder tissue components in rodents.…”

“…Experimental autoimmune cystitis (EAC) can be induced through immunization with bladder tissue components in rodents. These EAC models have been used to reproduce many clinical correlates of IC/BPS, offering a unique property for investigation of specific aspects of the disease such as cystitis pain and voiding dysfunction [10,23,24]. Using genetic engineering technology, we previously developed a transgenic EAC model (URO-OVA) that expresses the membrane form of the model antigen ovalbumin (OVA) as a self-antigen on the urothelium and develops bladder inflammation at 7–14 days after adoptive transfer of OVA-specific T cells for cystitis induction [25,26].…”

Activation of protease-activated receptor 4 of mast cells could downregulate proinflammatory cytokines in irritable bowel syndrome

“…Furthermore, when BMMCs were pretreated with supernatant from IBS-D mucosal biopsy samples6 for 60 min, PAR4-AP significantly decreased Agrin, CINC-1, CINC-2α, CINC-3, MCP-1 and TIMP-1 expression and increased Fas Ligand, Fractalkine, granulocyte macrophage colony-stimulating factor, IFN-γ, Leptin and IL-13 protein levels in supernatant-pretreated BMMCs (figure 2C). MCP-1 and MCs infiltration were previously identified in chronic visceral allodynia,7 and this can potentially be prevented by PAR4 agonism. However, these experiments were performed on cultured MCs that may have had a different phenotype compared with MCs residing in their natural microenvironment; these results may also be rat specific and may not reflect human MC physiology.…”

Kronik Prostatit/Kronik Pelvik Ağrı Sendromunda Etyoloji ve Tanı

“…Lokal olarak prostatta meydana gelen patoloji doku düzeyinde hassasiyet ve basınç oluşturmaktadır. Burada bahsedilen sitokinler ve kemokinler hücre sinyal molekülleridir ve gerek proinflamatuar, gerek inflamatuar gerekse de onarım sürecinde yer alan çok sayıda alt başlıkta incelenmektedir (45)(46)(47)(48)(49)(50). Bu hücre sinyalleri aracılığı ile lökositler artmakta ve ekstraprostatik sekresyonda (EPS) saptanmaktadır.…”