Hypothalamic AgRP neurons exert top-down control on systemic TNF-a release during endotoxemia.
Hypothalamic AgRP neurons exert top-down control on systemic TNF-a release during endotoxemia.
复制标题
下丘脑 AgRP 神经元在内毒素血症期间对全身 TNF-a 释放进行自上而下的控制。
DOI：
10.1016/j.cub.2022.09.017
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Boutagouga Boudjadja M
中科院分区：
文献类型：
--
作者：
Boutagouga Boudjadja M
食欲不振和能量负平衡是所有动物内毒素血症的共同特征，被认为通过减少对宿主和病原体新陈代谢的营养供应而起到保护作用。因此，禁食和限制卡路里具有良好的抗炎作用。然而，为了应对细胞和器官层面营养供应的减少，负能量平衡也招募了不同的能量感应大脑回路，但尚不清楚这些神经系统是否在其抗炎作用中发挥作用。在这里，我们报告了下丘脑AgRP神经元--负能量平衡中枢代表的关键神经元群--具有平行的免疫调节功能。我们发现，当空腹小鼠出现内毒素血症时，AgRP神经元的活动保持不变，但这种活动不影响进食行为和内毒素缺乏性厌食。此外，我们发现内毒素血症使AgRP神经元严重减敏，而AgRP神经元对抑制信号也变得不敏感。在喂养的小鼠中，通过化学激活来模拟这种持续的AgRP神经元活动--一种已知概括禁食核心行为特征的操作--会导致内毒素血症期间急性肿瘤坏死因子-α的释放减少。从机制上讲，我们发现内源性糖皮质激素起着重要的作用：银杏核神经元上糖皮质激素受体的缺失可以阻止内毒素血症引起的脱敏，更重要的是，它可以抵消禁食引起的肿瘤坏死因子-α释放的抑制，从而导致疾病的延长。综上所述，这些发现提供了直接将AgRP神经元活性与内毒素血症时的急性反应联系起来的证据，表明这些神经元是与负能量平衡和分解代谢相关的免疫调节效应的功能组成部分。
Loss of appetite and negative energy balance are common features of endotoxemia in all animals and are thought to have protective roles by reducing nutrient availability to host and pathogen metabolism. Accordingly, fasting and caloric restriction have well-established anti-inflammatory properties. However, in response to reduced nutrient availability at the cellular and organ levels, negative energy balance also recruits distinct energy-sensing brain circuits, but it is not known whether these neuronal systems have a role in its anti-inflammatory effects. Here, we report that hypothalamic AgRP neurons—a critical neuronal population for the central representation of negative energy balance—have parallel immunoregulatory functions. We found that when endotoxemia occurs in fasted mice, the activity of AgRP neurons remains sustained, but this activity does not influence feeding behavior and endotoxemic anorexia. Furthermore, we found that endotoxemia acutely desensitizes AgRP neurons, which also become refractory to inhibitory signals. Mimicking this sustained AgRP neuron activity in fed mice by chemogenetic activation—a manipulation known to recapitulate core behavioral features of fasting—results in reduced acute tumor necrosis factor alpha (TNF-α) release during endotoxemia. Mechanistically, we found that endogenous glucocorticoids play an important role: glucocorticoid receptor deletion from AgRP neurons prevents their endotoxemia-induced desensitization, and importantly, it counteracts the fasting-induced suppression of TNF-α release, resulting in prolonged sickness. Together, these findings provide evidence directly linking AgRP neuron activity to the acute response during endotoxemia, suggesting that these neurons are a functional component of the immunoregulatory effects associated with negative energy balance and catabolic metabolism.