Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States.
Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States.
Front Immunol. 2019 Apr 2;10:585. doi: 10.3389/fimmu.2019.00585. eCollection 2019.
The brain regulates physiological functions integral to survival. However, the insight into brain neuronal regulation of peripheral immune function and the neuromediator systems and pathways involved remains limited. Here, utilizing selective genetic and pharmacological approaches, we studied the role of forebrain cholinergic signaling in the regulation of peripheral immune function and inflammation. Forebrain-selective genetic ablation of acetylcholine release and vagotomy abolished the suppression of serum TNF by the centrally-acting cholinergic drug galantamine in murine endotoxemia. Selective stimulation of acetylcholine action on the M1 muscarinic acetylcholine receptor (M1 mAChR) by central administration of the positive allosteric modulator benzyl quinolone carboxylic acid (BQCA) suppressed serum TNF (TNFα) levels in murine endotoxemia. This effect was recapitulated by peripheral administration of the compound. BQCA also improved survival in murine endotoxemia and these effects were abolished in M1 mAChR knockout (KO) mice. Selective optogenetic stimulation of basal forebrain cholinergic neurons innervating brain regions with abundant M1 mAChR localization reduced serum TNF in endotoxemic mice. These findings reveal that forebrain cholinergic neurons regulate innate immune responses and inflammation, suggesting the possibility that in diseases associated with cholinergic dysfunction, including Alzheimer's disease this anti-inflammatory regulation can be impaired. These results also suggest novel anti-inflammatory approaches based on targeting forebrain cholinergic signaling in sepsis and other disorders characterized by immune dysregulation.
大脑调节着对生存至关重要的生理功能。然而，人们对于大脑神经元如何调节外周免疫功能以及涉及的神经递质系统和途径的了解仍然有限。在这里，我们利用选择性基因和药理学方法，研究了前脑胆碱能信号在调节外周免疫功能和炎症中的作用。选择性基因敲除前脑乙酰胆碱释放和迷走神经切断术消除了中枢作用的胆碱能药物加兰他敏对小鼠内毒素血症中血清 TNF 的抑制作用。通过中枢给予正变构调节剂苯并喹诺羧酸（BQCA）选择性刺激乙酰胆碱对 M1 毒蕈碱乙酰胆碱受体（M1 mAChR）的作用，抑制了小鼠内毒素血症中的血清 TNF（TNFα）水平。该化合物的外周给药也可重现这种效果。BQCA 还改善了小鼠内毒素血症的存活率，而在 M1 mAChR 敲除（KO）小鼠中这些效果被消除。选择性光遗传学刺激支配富含 M1 mAChR 定位的脑区的基底前脑胆碱能神经元可降低内毒素血症小鼠的血清 TNF。这些发现表明，前脑胆碱能神经元调节先天免疫反应和炎症，这表明在与胆碱能功能障碍相关的疾病中，包括阿尔茨海默病，这种抗炎调节可能受损。这些结果还表明，基于针对败血症和其他以免疫失调为特征的疾病中的前脑胆碱能信号的新型抗炎方法是可行的。
