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

离子通道 TRPA1 是抑制脓毒症炎症所必需的

• 批准号: 10356812
• 负责人: Sangeeta S. Chavan
• 金额: $ 33.5万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356812
• 关键词: Acetylcholine; Action Potentials; Activated Lymphocyte; Activation Analysis; Address; Afferent Neurons; Agonist; Animals; Ankyrin Repeat; Anti-Inflammatory Agents; Binding; Binding Proteins; Biological Assay; Brain; Brain Stem; Calcium; Cause of Death; Cells; Clinical Trials; Data; Disease; Disease Progression; Electric Stimulation; Electrophysiology (science); Endotoxemia; Fiber; Functional disorder; Generations; Homeostasis; Immune; Immune response; Immune system; Immunohistochemistry; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Innate Immune Response; Interleukin-1; Ion Channel; Knockout Mice; Knowledge; Ligation; Measurement; Mediating; Medical; Methods; Modality; Molecular; Motor; Mouse Strains; Mus; Nerve; Nerve Fibers; Nervous System control; Neuroimmune; Neurons; Neurotransmitters; Nicotinic Receptors; Organ; Pathogenesis; Pathway interactions; Patients; Peripheral; Play; Prevention; Production; Proteins; Public Health; Reflex action; Research; Research Design; Rheumatoid Arthritis; Rodent Model; Role; Sensory; Sepsis; Septic Shock; Signal Transduction; Spleen; Structure of splenic vein; Surface Plasmon Resonance; TNF gene; TRPA channel; Testing; Therapeutic; Time; Transgenic Organisms; Travel; United States; Vagus nerve structure; Visceral; base; brain pathway; calcium indicator; cytokine; design; experimental study; immunoregulation; improved; innovation; insight; macrophage; mind control; monocyte; neural circuit; neurophysiology; neurotransmission; neurotransmitter release; novel; novel strategies; novel therapeutics; patch clamp; polymicrobial sepsis; receptor; relating to nervous system; response; therapeutic target; tool

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.

抽象的 败血症代表着巨大的未满足医疗需求：它每年都会折磨近100万个人 美国，杀死> 200,000。败血症和其他炎症的病理生理 疾病是由固有免疫调查失调和绝对升高的疾病介导的 细胞因子水平。炎症反射由一个由感觉组成的神经免疫电路组成 （传入）和运动（传出）迷走神经元调节脾脏中细胞因子的产生。 电动机弧的分子机制是很好的，但对 炎症反射的感觉弧。在电动机弧中，迷走神经中会有动作电位 神经，在脾神经中行进，并在被激活以产生的淋巴细胞上达到顶峰 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烟碱乙酰胆碱受体（7NACHR），在巨噬细胞和单核细胞上表达。 使用新型的电生理记录和解码方法，我们最近确定了 迷走神经中的细胞因子特异性感觉神经元信号。这些研究揭示了一个新颖的作用 对于离子通道，瞬态接收器电势arnkyrin-repeat 1（trpa1），在传入迷走神经 对IL-1的神经反应，以及迷走神经中TRPA1传入纤维的选择性激活， 这也抑制内毒素血症中的TNF水平。在这里，我们假设TRPA1扮演 在介导白介素-1（IL-1）诱导的迷走神经激活和选择性中的重要作用 刺激表达迷走神经纤维的TRPA1将改善生存和病理生理学 败血症。该假设将在以下两个具体目的中解决：特定目标1。 阐明TRPA1在介导IL-1诱导的炎症反射激活中的作用。 特定目的2。评估迷走神经活动的动态并评估选择性的影响 TRPA1刺激败血症的生存和病理生理学。我们建议利用小说 整合实验评估的方法直接结合和TRPA1的共定位与 在感觉神经元上的IL-1R，神经元中的动作电位产生分析以及评估 TRPA1依赖性病理生理作用在受败血症的动物中的作用。这 重大的新研究将为创新分子提供新颖而有影响力的数据 炎症反射的传入（感觉）弧的机理及其在败血症中的作用。这个数据 将为开发新颖的治疗方式铺平道路，以预防和治疗 败血症/败血性休克。

项目成果

Involvement of Neural Transient Receptor Potential Channels in Peripheral Inflammation.

• DOI: 10.3389/fimmu.2020.590261
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Silverman HA;Chen A;Kravatz NL;Chavan SS;Chang EH
• 通讯作者: Chang EH

Targeted peripheral focused ultrasound stimulation attenuates obesity-induced metabolic and inflammatory dysfunctions.

• DOI: 10.1038/s41598-021-84330-6
• 发表时间: 2021-03-03
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Huerta TS;Devarajan A;Tsaava T;Rishi A;Cotero V;Puleo C;Ashe J;Coleman TR;Chang EH;Tracey KJ;Chavan SS
• 通讯作者: Chavan SS

Control of inflammation using non-invasive neuromodulation: past, present and promise.

• DOI: 10.1093/intimm/dxab073
• 发表时间: 2022-01-22
• 期刊: International immunology
• 影响因子: 4.4
• 作者: Tynan A;Brines M;Chavan SS
• 通讯作者: Chavan SS