The ion channel TRPA1 is required for suppression of inflammation in sepsis

摘要 败血症是一种巨大的未得到满足的医疗需求：每年有近100万人在 美国，杀死了20万人。脓毒症和其他炎症性疾病的病理生理 疾病是由调节失调的先天免疫反应和异常升高的 细胞因子水平。炎症反射由神经免疫回路组成，该回路由感觉神经 (传入)和运动(传出)迷走神经，调节脾中细胞因子的产生。这个 马达电弧的分子机制已被很好地定义，但对其知之甚少 炎症反射的感觉弧线。在运动弧中，迷走神经产生动作电位。 神经，在脾神经中移动，并在淋巴细胞上达到顶峰，淋巴细胞被激活以产生 乙酰胆碱，一种神经递质分子，通过信号传导抑制细胞因子的产生 7烟碱型乙酰胆碱受体(7nAChR)，表达于巨噬细胞和单核细胞。 使用新的电生理记录和解码方法，我们最近发现 迷走神经中细胞因子特有的感觉神经信号。这些研究揭示了一个新的角色 对于离子通道，传入迷走神经中的瞬时受体电位锚蛋白重复1(TRPA1) 对IL-1的神经反应和迷走神经中TRPA 1传入纤维的选择性激活， 它还能抑制内毒素血症中的肿瘤坏死因子水平。在这里，我们假设TRPA1扮演一个 在介导IL-1(IL-1)诱导的迷走神经激活中的基本作用和选择性 刺激表达TRPA1的迷走神经纤维将改善大鼠的存活和病理生理 败血症。这一假设将在以下两个具体目标中加以阐述：具体目标1。 阐明TRPA1在IL-1诱导的炎症反射激活中的作用。 具体目标2.评估迷走神经活动的动力学和评价选择性 TRPA1刺激对脓毒症患者生存和病理生理的影响。我们打算用一本小说 将评估TRPA1与 IL-1受体在感觉神经元上的表达，神经元动作电位产生的分析和评价 依赖TRPA1的病理生理效应在脓毒症动物中的作用。这 重大的新研究将为创新的分子提供新的和有影响力的数据 炎症反射的传入(感觉)弧的机制及其在脓毒症中的作用。此数据 将为开发新的治疗方式预防和治疗 败血症/感染性休克。

Abstract Sepsis represents a huge unmet medical need: it annually afflicts nearly 1 million individuals in the United States, killing >200,000. The pathophysiology of sepsis and other inflammatory disorders is mediated by dysregulated innate immune responses and abnormally elevated cytokine levels. The inflammatory reflex consists of a neural-immune circuit composed of sensory (afferent) and motor (efferent) vagal neurons that regulate cytokine production in the spleen. The molecular mechanisms of the motor arc are well defined, but considerably less is known about the sensory arc of the inflammatory reflex. In the motor arc, action potentials arise in the vagus nerve, travel in the splenic nerve, and culminate on lymphocytes that are activated to produce acetylcholine, a neurotransmitter molecule that inhibits cytokine production via signaling through 7 nicotinic acetylcholine receptor (7nAChR), expressed on macrophages and monocytes. Using novel electrophysiological recording and decoding methods, we recently identified cytokine-specific sensory neural signals in the vagus nerve. These studies revealed a novel role for an ion channel, transient receptor potential ankyrin-repeat 1 (TRPA1), in the afferent vagus nerve response to IL-1, and selective activation of TRPA1 afferent fibers in the vagus nerve, which also suppresses TNF levels in endotoxemia. Here, we hypothesize that TRPA1 plays an essential role in mediating interleukin-1 (IL-1)-induced vagus nerve activation, and selective stimulation of TRPA1 expressing vagus nerve fibers will improve survival and pathophysiology in sepsis. This hypothesis will be addressed in the following two Specific Aims: Specific Aim 1. Elucidate the role of TRPA1 in mediating IL-1-induced activation of the inflammatory reflex. Specific Aim 2. Assess the dynamics of vagus nerve activity and evaluate the effects of selective TRPA1 stimulation on survival and pathophysiology in sepsis. We propose to utilize a novel approach that integrates experiments assessing direct binding and colocalization of TRPA1 with IL-1Rs on the sensory neurons, analysis of action potential generation in neurons, and evaluating the role of TRPA1-dependent pathophysiological effects in animals subjected to sepsis. This significant new research will provide novel and impactful data for an innovative molecular mechanism of the afferent (sensory) arc of the inflammatory reflex and its role in sepsis. This data will pave the way to develop novel therapeutic modalities for the prevention and treatment of sepsis/septic shock.