Nociceptor Neurons are Involved in the Host Response to Escherichia coli Urinary Tract Infections.
Nociceptor Neurons are Involved in the Host Response to Escherichia coli Urinary Tract Infections.
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伤害感受器神经元参与宿主对大肠杆菌尿路感染的反应
DOI：
10.2147/jir.s356960
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发表时间：
2022
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
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作者：
尿路感染（uti）可引起快速的宿主免疫反应，导致膀胱炎症和上皮损伤。神经免疫相互作用是调节粘膜组织免疫功能的关键。然而，伤害感受器神经元在膀胱宿主防御中的作用尚未明确。本研究旨在探讨尿路感染时伤害感受神经元与膀胱免疫系统的相互作用。本研究检测尿路致病性大肠杆菌（UPEC）和脂多糖（LPS）是否能直接刺激伤害感受器神经元。雌性C57BL/6J小鼠用高剂量辣椒素（一种高亲和力TRPV1激动剂）治疗损伤感受器神经元。观察UPEC感染后膀胱炎症、屏障上皮功能及膀胱免疫细胞浸润情况。检测感染膀胱中神经肽降钙素基因相关肽（CGRP）水平。此外，在体外和体内研究了CGRP对中性粒细胞和巨噬细胞的影响。我们发现UPEC及其致病因子LPS可直接激活伤害受体神经元，释放CGRP进入感染膀胱，抑制中性粒细胞的募集，抑制巨噬细胞的极化，抑制UPEC的杀伤功能。肉毒杆菌神经毒素A （BoNT/A）和BIBN4096 （CGRP拮抗剂）均能阻断神经元抑制作用，防止upc感染。本研究揭示了UPEC刺激伤害感受器神经元分泌CGRP抑制先天免疫的新机制。
Urinary tract infections (UTIs) can evoke a rapid host immune response leading to bladder inflammation and epithelial damage. Neuroimmune interactions are critical for regulating immune function in mucosal tissues. Yet the role of nociceptor neurons in bladder host defense has not been well defined. This study aimed to explore the interaction between nociceptor neurons and bladder immune system during UTIs. In this study, whether uropathogenic Escherichia coli (UPEC) and lipopolysaccharide (LPS) can directly stimulate nociceptor neurons was detected. Female C57BL/6J mice were treated with high dose of capsaicin, a high-affinity TRPV1 agonist, to ablate nociceptor neurons. Bladder inflammation, barrier epithelial function and bladder immune cell infiltration were assessed after UPEC infection. The level of neuropeptide calcitonin gene-related peptide (CGRP) in infected bladder was detected. Furthermore, the effects of CGRP on neutrophils and macrophages were evaluated both in vitro and in vivo. We found that UPEC and its pathogenic factor LPS could directly excite nociceptor neurons, releasing CGRP into infected bladder, which suppressed the recruitment of neutrophils, the polarization of macrophages and the killing function of UPEC. Both Botulinum neurotoxin A (BoNT/A) and BIBN4096 (CGRP antagonism) blocked neuronal inhibition and prevented against UPEC infection. The present study showed a novel mechanism by which UPEC stimulated the secretion of CGRP from nociceptor neurons to suppress innate immunity.