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.

摘要 脓毒症代表了一个巨大的未满足的医疗需求：它每年折磨着近100万人， 美国，死亡超过20万人。脓毒症和其他炎症性疾病的病理生理学 疾病是由先天免疫应答失调和异常升高介导的。 细胞因子水平。炎症反射由神经免疫回路组成， （传入）和运动（传出）迷走神经元，其调节脾中的细胞因子产生。的 马达电弧的分子机制已经很好地定义，但对马达电弧的分子机制知之甚少。 炎症反射的感觉弧。在运动弧中，迷走神经产生动作电位 神经，在脾神经中旅行，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，通过以下途径抑制细胞因子的产生： 在巨噬细胞和单核细胞上表达的烟碱乙酰胆碱受体（nAChR）。 使用新的电生理记录和解码方法，我们最近发现， 迷走神经中的多巴胺特异性感觉神经信号。这些研究揭示了一种新的作用 对于传入迷走神经中的离子通道，瞬时受体电位锚定重复1（TRPA 1）， 对IL-1 β的神经反应，以及迷走神经中TRPA 1传入纤维的选择性激活， 其还抑制内毒素血症中的TNF水平。在这里，我们假设TRPA 1发挥作用， 在介导白细胞介素-1 β（IL-1 β）诱导的迷走神经激活中起重要作用， 刺激表达TRPA 1的迷走神经纤维将改善神经系统的存活和病理生理学。 败血症这一假设将在以下两个具体目标中得到解决：具体目标1。 阐明TRPA 1在介导IL-1 β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，并评估选择性 TRPA 1刺激对脓毒症中的存活和病理生理学的影响我们打算用一本小说 一种整合了评估TRPA 1与 IL-1 Rs对感觉神经元的作用，神经元中动作电位产生的分析，以及评估 TRPA 1依赖性病理生理效应在脓毒症动物中的作用。这 重要的新研究将为创新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。该数据 将为开发新的治疗方式， 脓毒症/脓毒性休克。

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