Meseguer Victor, Alpizar Yeranddy A, Luis Enoch, Tajada Sendoa, Denlinger Bristol, Fajardo Otto, Manenschijn Jan-Albert, Fernández-Peña Carlos, Talavera Arturo, Kichko Tatiana, Navia Belén, Sánchez Alicia, Señarís Rosa, Reeh Peter, Pérez-García María Teresa, López-López José Ramón, Voets Thomas, Belmonte Carlos, Talavera Karel, Viana Félix
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández y CSIC, Alicante E-03550, Spain.
Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine and TRP Research Platform Leuven (TRPLe), Leuven B-3000, Belgium.
Nat Commun. 2014;5:3125. doi: 10.1038/ncomms4125.
Gram-negative bacterial infections are accompanied by inflammation and somatic or visceral pain. These symptoms are generally attributed to sensitization of nociceptors by inflammatory mediators released by immune cells. Nociceptor sensitization during inflammation occurs through activation of the Toll-like receptor 4 (TLR4) signalling pathway by lipopolysaccharide (LPS), a toxic by-product of bacterial lysis. Here we show that LPS exerts fast, membrane delimited, excitatory actions via TRPA1, a transient receptor potential cation channel that is critical for transducing environmental irritant stimuli into nociceptor activity. Moreover, we find that pain and acute vascular reactions, including neurogenic inflammation (CGRP release) caused by LPS are primarily dependent on TRPA1 channel activation in nociceptive sensory neurons, and develop independently of TLR4 activation. The identification of TRPA1 as a molecular determinant of direct LPS effects on nociceptors offers new insights into the pathogenesis of pain and neurovascular responses during bacterial infections and opens novel avenues for their treatment.
革兰氏阴性菌感染伴随着炎症以及躯体或内脏疼痛。这些症状通常归因于免疫细胞释放的炎症介质使伤害感受器致敏。炎症期间伤害感受器的致敏是通过脂多糖（LPS）激活Toll样受体4（TLR4）信号通路实现的，LPS是细菌裂解的有毒副产物。在这里，我们表明LPS通过TRPA1发挥快速、膜限定的兴奋性作用，TRPA1是一种瞬时受体电位阳离子通道，对于将环境刺激转化为伤害感受器活动至关重要。此外，我们发现疼痛和急性血管反应，包括由LPS引起的神经源性炎症（降钙素基因相关肽释放）主要依赖于伤害性感觉神经元中TRPA1通道的激活，并且独立于TLR4激活而发生。将TRPA1鉴定为LPS对伤害感受器直接作用的分子决定因素，为细菌感染期间疼痛和神经血管反应的发病机制提供了新见解，并为其治疗开辟了新途径。
