Transient Receptor Potential Ankyrin-1-expressing vagus nerve fibers mediate IL-1β induced hypothermia and reflex anti-inflammatory responses.
Transient Receptor Potential Ankyrin-1-expressing vagus nerve fibers mediate IL-1β induced hypothermia and reflex anti-inflammatory responses.
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DOI：
10.1186/s10020-022-00590-6
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发表时间：
2023-01-18
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炎症是对感染和损伤的生理反应，由免疫和神经系统协调。炎症反应中产生的白介素1β(IL-1β)和其他细胞因子激活感觉神经元(伤害性感受器)，介导疼痛、疾病行为和代谢反应的发生。尽管表达瞬时受体电位Ankyrin-1(TRPA1)的伤害性感受器可以启动炎症反应，但关于TRPA1在特定细胞因子的生理反应中的作用还知之甚少。为了监测清醒和无拘无束小鼠的体温，在小鼠的腹膜腔内植入遥测探头。使用转基因和组织特异性基因敲除和化学发生技术，我们记录了对强大的促炎细胞因子IL-1β的温度反应。通过钙离子成像、全细胞膜片钳和全神经记录，我们研究了TRPA1在IL-1β介导的神经元激活中的作用。用小鼠急性内毒素血症和脓毒症模型来阐明光遗传学和化学遗传学的特异性激活或TRPA1神经元的消融如何影响炎性损伤的结果。所有统计检验均使用GraphPad Prism 9软件进行，对于所有分析，P ≤ 0.05被认为具有统计学意义。在这里，我们描述了一种以前未知的机制，通过IL-1β激活传入迷走神经纤维来触发低温，这一反应可通过选择性沉默神经元TRPA1来取消。传入迷走神经TRPA1信号也可抑制内毒素刺激的细胞因子风暴，显著降低细菌败血症的致死率。因此，IL-1β在反射性抗炎反应的传入臂激活TRPA1迷走神经信号，抑制细胞因子的释放，诱导低温，降低感染的死亡率。这一发现证实，TRPA1是一种离子通道，以前被认为是寒冷、疼痛、瘙痒和各种有害分子的促炎探测器，它也通过激活反射性抗炎活性发挥着特定的抗炎作用。网上版载有补充材料，可在10.1186/s10020-022-00590-6查阅。
Inflammation, the physiological response to infection and injury, is coordinated by the immune and nervous systems. Interleukin-1β (IL-1β) and other cytokines produced during inflammatory responses activate sensory neurons (nociceptors) to mediate the onset of pain, sickness behavior, and metabolic responses. Although nociceptors expressing Transient Receptor Potential Ankyrin-1 (TRPA1) can initiate inflammation, comparatively little is known about the role of TRPA1 nociceptors in the physiological responses to specific cytokines. To monitor body temperature in conscious and unrestrained mice, telemetry probes were implanted into peritoneal cavity of mice. Using transgenic and tissue specific knockouts and chemogenetic techniques, we recorded temperature responses to the potent pro-inflammatory cytokine IL-1β. Using calcium imaging, whole cell patch clamping and whole nerve recordings, we investigated the role of TRPA1 during IL-1β-mediated neuronal activation. Mouse models of acute endotoxemia and sepsis were used to elucidate how specific activation, with optogenetics and chemogenetics, or ablation of TRPA1 neurons can affect the outcomes of inflammatory insults. All statistical tests were performed with GraphPad Prism 9 software and for all analyses, P ≤ 0.05 was considered statistically significant. Here, we describe a previously unrecognized mechanism by which IL-1β activates afferent vagus nerve fibers to trigger hypothermia, a response which is abolished by selective silencing of neuronal TRPA1. Afferent vagus nerve TRPA1 signaling also inhibits endotoxin-stimulated cytokine storm and significantly reduces the lethality of bacterial sepsis. Thus, IL-1β activates TRPA1 vagus nerve signaling in the afferent arm of a reflex anti-inflammatory response which inhibits cytokine release, induces hypothermia, and reduces the mortality of infection. This discovery establishes that TRPA1, an ion channel known previously as a pro-inflammatory detector of cold, pain, itch, and a wide variety of noxious molecules, also plays a specific anti-inflammatory role via activating reflex anti-inflammatory activity. The online version contains supplementary material available at 10.1186/s10020-022-00590-6.
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DOI：
10.1523/jneurosci.3795-08.2008
发表时间：
2008-12-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
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作者：
Binshtok AM;Wang H;Zimmermann K;Amaya F;Vardeh D;Shi L;Brenner GJ;Ji RR;Bean BP;Woolf CJ;Samad TA
通讯作者：
Samad TA
影响因子：
4.6
作者：
Gentry, Clive;Andersson, David A.;Bevan, Stuart
通讯作者：
Bevan, Stuart
影响因子：
64.5
作者：
Chang RB;Strochlic DE;Williams EK;Umans BD;Liberles SD
通讯作者：
Liberles SD
影响因子：
5.6
作者：
通讯作者：
--
影响因子：
6.1
作者：
Chang Q;Martin LJ
通讯作者：
Martin LJ