Cystitis-induced bladder pain is Toll-like receptor 4 dependent in a transgenic autoimmune cystitis murine model: a MAPP Research Network animal study
Cystitis-induced bladder pain is Toll-like receptor 4 dependent in a transgenic autoimmune cystitis murine model: a MAPP Research Network animal study
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DOI：
10.1152/ajprenal.00017.2019
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发表时间：
2019-07-01
影响因子：
4.2
通讯作者：
Luo, Yi
中科院分区：
文献类型：
--
作者：
Cui, Xiangrong;Jing, Xuan;Luo, Yi
Toll 样受体 (TLR)4 激活的改变已在几种慢性疼痛病症中被发现，但在间质性膀胱炎/膀胱疼痛综合征 (IC/BPS) 中尚未得到充分研究。我们之前发表的人类研究表明，IC/BPS 患者表现出改变的全身 TLR4 介导的炎症反应，这与报告的疼痛严重程度显着相关。在本研究中，我们试图使用我们经过验证的 IC/BPS 样转基因自身免疫性膀胱炎模型 (URO-OVA) 来确定 TLR4 激活的改变是否在 IC/BPS 患者的盆腔/膀胱疼痛中发挥作用。 URO-OVA 小鼠在诱导膀胱炎后出现与骨盆和膀胱疼痛一致的反应，这与 TLR4 介导的促炎细胞因子 IL-1β、IL-6 和 TNF-α 的脾细胞产生增加有关。诱导膀胱炎后，还观察到促炎细胞因子 IL-6 和 TNF-α、神经胶质活化标记物 CD11b 和神经胶质纤维酸性蛋白以及内源性 TLR4 配体高迁移率族蛋白 1 的 mRNA 脊髓表达增加。与 URO-OVA 小鼠相比，TLR4 缺陷的 URO-OVA 小鼠在诱导膀胱炎后，尽管有相似的膀胱炎症和排尿功能障碍，但伤害性反应显着减少。静脉注射 TAK-242（一种 TLR4 选择性拮抗剂）可显着减弱膀胱炎诱导的 URO-OVA 小鼠的伤害性反应，这与 TLR4 介导的 IL-1β、IL-6 的脾细胞产生减少有关。和 TNF-α 以及 IL-6、TNF-α、CD11b 的 mRNA 脊髓表达减少。胶质纤维酸性蛋白和高迁移率族盒 1。我们的结果表明，在 URO-OVA 模型中，改变的 TLR4 激活在膀胱伤害感受中发挥着关键作用，与炎症和排尿功能障碍无关，为 IC/BPS 疼痛提供了潜在的机制见解和治疗靶点。
Altered Toll-like receptor (TLR)4 activation has been identified in several chronic pain conditions but has not been well studied in interstitial cystitis/bladder pain syndrome (IC/BPS). Our previously published human studies indicated that patients with IC/BPS present altered systemic TLR4-mediated inflammatory responses, which were significantly correlated with reported pain severity. In the present study, we sought to determine whether altered TLR4 activation plays a role in pelvic/bladder pain seen in patients with IC/BPS using our validated IC/BPS-like transgenic autoimmune cystitis model (URO-OVA). URO-OVA mice developed responses consistent with pelvic and bladder pain after cystitis induction, which was associated with increased splenocyte production of TLR4-mediated proinflammatory cytokines IL-1 beta, IL-6, and TNF-alpha. Increased spinal expression of mRNAs for proinflammatory cytokines IL-6 and TNF-alpha, glial activation markers CD11b and glial fibrillary acidic protein, and endogenous TLR4 ligand high mobility group box 1 was also observed after cystitis induction. Compared with URO-OVA mice, TLR4-deficient URO-OVA mice developed significantly reduced nociceptive responses, although similar bladder inflammation and voiding dysfunction, after cystitis induction. Intravenous administration of TAK-242 (a TLR4-selective antagonist) significantly attenuated nociceptive responses in cystitis-induced URO-OVA mice, which was associated with reduced splenocyte production of TLR4-mediated IL-1 beta, IL-6. and TNF-alpha as well as reduced spinal expression of mRNAs for IL-6, TNF-alpha, CD11b. glial fibrillary acidic protein, and high mobility group box 1. Our results indicate that altered TLR4 activation plays a critical role in bladder nociception independent of inflammation and voiding dysfunction in the URO-OVA model, providing a potential mechanistic insight and therapeutic target for IC/BPS pain.