Neuregulin-1-ErbB signaling promotes microglia activation contributing to mechanical allodynia of cyclophosphamide-induced cystitis
Neuregulin-1-ErbB signaling promotes microglia activation contributing to mechanical allodynia of cyclophosphamide-induced cystitis
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Neuregulin-1-ErbB 信号传导促进小胶质细胞活化，导致环磷酰胺诱导的膀胱炎的机械异常性疼痛
DOI：
10.1002/nau.24005
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发表时间：
2019-06-01
影响因子：
2
通讯作者：
Zhou, Xiang-Fu
中科院分区：
文献类型：
--
作者：
Chen, Jia-Liang;Zhou, Xin;Zhou, Xiang-Fu
目的中枢敏化在环磷酰胺诱发的膀胱炎中起重要作用。此外，CYP诱导的慢性疼痛作为一种内脏痛，与神经病理性疼痛有着共同的病理生理机制。以前的研究表明，神经调节蛋白-1（Nrg 1）-ErbB信号有助于神经性疼痛，但这种信号是否以及如何影响CYP诱导的膀胱炎中的机械性异常性疼痛尚不清楚。本研究旨在确定Nrg 1-ErbB信号传导是否以及如何调节CYP诱导的膀胱炎大鼠模型中的机械性异常性疼痛。方法采用大鼠膀胱疼痛综合征/间质性膀胱炎（BPS/IC）模型，采用腹腔注射法复制BPS/IC模型。鞘内注射不可逆ErbB家族受体抑制剂PD 168393和外源性Nrg 1以调节Nrg 1-ErbB信号传导。使用von-Frey细丝使用上下法评估下腹部的机械性异常性疼痛。采用免疫印迹法和免疫荧光染色法检测L 6-S1脊髓背角（SDH）中Nrg 1-ErbB信号通路、Iba-1、p-p38和IL-1 β的表达。结果膀胱炎组SDH中Nrg 1-ErbB信号上调，小胶质细胞活化标志物Iba-1和p-p38以及促炎因子白细胞介素-1 β（IL-1 β）过表达。此外，用PD 168393治疗减轻CYP诱导的膀胱炎中的机械性异常性疼痛并抑制小胶质细胞活化，导致IL-1 β的产生减少。抑制剂PD 168393逆转了外源性Nrg 1对膀胱炎模型的镇痛作用。结论Nrg 1-ErbB信号通路可能促进小胶质细胞活化，参与CYP诱导的膀胱炎机械性异常性疼痛的发生。我们的研究表明，调节Nrg 1-ErbB信号可能对治疗BPS/IC的疼痛症状具有治疗价值。
Aims Central sensitization playsimportant roles in cyclophosphamide (CYP)-induced cystitis. In addition, as a visceral pain, CYP-induced chronic pain shares common pathophysiological mechanisms with neuropathic pain. Previous studies demonstrated that neuregulin-1 (Nrg1)-ErbB signaling contributes to neuropathic pain, but whether and how this signaling influences mechanical allodynia in CYP-induced cystitis is unclear. This study aimed to determine whether and how Nrg1-ErbB signaling modulates mechanical allodynia in a CYP-induced cystitis rat model. Methods Systemic injection with CYP was used to establish a rat model of bladder pain syndrome/interstitial cystitis (BPS/IC). An irreversible ErbB family receptor inhibitor, PD168393, and exogenous Nrg1 were intrathecally injected to modulate Nrg1-ErbB signaling. Mechanical allodynia in the lower abdomen was assessed with von-Frey filaments using the up-down method. Western blot analysis and immunofluorescence staining were used to measure the expression of Nrg1-ErbB signaling, Iba-1, p-p38, and IL-1 beta in the L6-S1 spinal dorsal horn (SDH). Results We observed upregulation of Nrg1-ErbB signaling as well as overexpression of the microglia activation markers Iba-1 and p-p38 and the proinflammatory factor, interleukin-1 beta (IL-1 beta), in the SDH of the cystitis group. Further, treatment with PD168393 attenuated mechanical allodynia in CYP-induced cystitis and inhibited microglia activation, leading to decreased production of IL-1 beta. The inhibitor PD168393 reversed the algesic effect of exogenous Nrg1 on the cystitis model. Conclusions Nrg1-ErbB signaling may promote microglia activation, contributing to mechanical allodynia of CYP-induced cystitis. Our study showed that modulation of Nrg1-ErbB signaling may have therapeutic value for treating pain symptoms in BPS/IC.