Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Pain. 2017 Aug;158(8):1538-1545. doi: 10.1097/j.pain.0000000000000947.
Toll-like receptor 7 (TLR7) is associated with the pathophysiology of systemic lupus erythematosus and Sjögren syndrome, well-known diseases accompanying interstitial cystitis (IC). We studied TLR7 expression in the bladder of patients with Hunner-type IC (HIC) and its functional roles in bladder inflammation and nociception using mice. Bladder biopsy specimens were obtained from patients with HIC. Specimens from the noncancerous portion of the bladder of patients with bladder cancer served as controls. The specimens were examined by immunohistochemistry and real-time polymerase chain reaction of TLR7. Loxoribine (LX), a TLR7 agonist, was instilled in the bladder of C57BL/6N female mice, and TLR7-mRNA expression and histological changes of the bladder, bladder pain-like licking behavior, voiding behavior, cystometry, and bladder afferent nerve activities were investigated. The effects of hydroxychloroquine, a TLR7 antagonist, on the LX-induced changes on cystometry and voiding behavior were studied. The number of TLR7 immuno-reactive cells and the mRNA expression of TLR7 were significantly increased in HIC specimens. Intravesical instillation of LX induced edema, congestion, inflammation, and significantly increased TLR7-mRNA expression in the mouse bladder. Loxoribine-instillation also significantly increased licking behavior, voiding frequency, and afferent nerve activities associated with decreased single-voided volume and intercontraction interval of micturitions. Hydroxychloroquine reversed the LX-induced cystometric and voiding behavioral changes. Toll-like receptor 7 was up-regulated in the bladder mucosa of patients with HIC, and activation of TLR7 in the mouse bladder induced cystitis with sensory hyperactivity of the bladder. Blocking the TLR7 pathway may be an innovative treatment target of HIC.
Toll 样受体 7（TLR7）与系统性红斑狼疮和干燥综合征的病理生理学有关，这两种疾病是伴随间质性膀胱炎（IC）的已知疾病。我们使用小鼠研究了 Hunner 型 IC（HIC）患者膀胱中 TLR7 的表达及其在膀胱炎症和痛觉中的功能作用。从 HIC 患者获得膀胱活检标本。膀胱癌患者膀胱非癌部分的标本作为对照。通过 TLR7 的免疫组织化学和实时聚合酶链反应检查标本。TLR7 激动剂洛索利嗪（LX）被注入 C57BL/6N 雌性小鼠的膀胱中，研究了 TLR7-mRNA 表达和膀胱的组织学变化、膀胱痛觉样舔舐行为、排尿行为、膀胱测压和膀胱传入神经活动。研究了 TLR7 拮抗剂羟氯喹对 LX 诱导的膀胱测压和排尿行为变化的影响。HIC 标本中 TLR7 免疫反应细胞的数量和 TLR7 的 mRNA 表达明显增加。膀胱内注入 LX 可诱导小鼠膀胱水肿、充血、炎症，并显著增加 TLR7-mRNA 表达。LX 灌洗还显著增加了舔舐行为、排尿频率以及与单次排尿量减少和排尿间收缩间隔缩短相关的传入神经活动。羟氯喹逆转了 LX 诱导的膀胱测压和排尿行为变化。HIC 患者膀胱黏膜中 TLR7 上调，小鼠膀胱中 TLR7 的激活可引起膀胱炎，并使膀胱感觉过敏。阻断 TLR7 途径可能是 HIC 的一种创新治疗靶点。
