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
复制标题
DOI：
10.1152/ajprenal.00202.2014
复制
发表时间：
2015-01-15
影响因子：
4.2
通讯作者：
Daneshgari, Firouz
中科院分区：
文献类型：
--
作者：
Bicer, Fuat;Altuntas, Cengiz Z.;Daneshgari, Firouz
间质性膀胱炎/膀胱疼痛综合征（IC/PBS）中慢性盆腔疼痛的原因尚不清楚;自身免疫是一种可能的病因。我们最近已经表明，注射尿斑蛋白3A（UPK 3A 65-84）的单一免疫原性肽在雌性BALB/cJ小鼠中诱导实验性自身免疫性膀胱炎（EAC），这在准确反映IC/PBS的泌尿症状和骨盆疼痛的实验模型中是独特的。本项目的目的是确定肥大细胞和肥大细胞趋化因子/激活剂单核细胞趋化蛋白-1 [趋化因子（C-C基序）配体2（CCL 2）]在该模型中的异常性疼痛中的作用。我们用UPK 3A 65-84肽免疫6- 8周龄雌性BALB/cJ小鼠，5-40天后，观察到与单独注射佐剂的小鼠相比，对用von Frey单丝刺激耻骨上腹部和后爪表面的反应增加。EAC小鼠的耻骨上和后爪触觉异常性疼痛反应通过将利多卡因滴注到膀胱中而不是通过在子宫中滴注利多卡因而被阻断，证实膀胱是超敏反应的来源。用UPK 3A 65-84免疫后，在膀胱中发现活化肥大细胞的数量和CCL 2的表达显著增加。肥大细胞稳定剂克罗维因钠和组胺受体1和2的拮抗剂抑制过敏反应。此外，缺失Ccl 2或趋化因子（C-C基序）受体2基因的BALB/cJ小鼠在UPK 3A 65-84免疫后表现出显著降低的异常性疼痛和肥大细胞积累。这些结果表明，UPK 3A 65-84免疫引起慢性内脏异常性疼痛，并表明其由膀胱中CCL 2驱动的肥大细胞积累介导。
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.