Department of Biomedical Sciences and Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
Pharmacol Ther. 2017 Nov;179:1-16. doi: 10.1016/j.pharmthera.2017.05.002. Epub 2017 May 18.
The nervous system and immune system have broad and overlapping distributions in the body, and interactions of these ubiquitous systems are central to the field of neuroimmunology. Over the past two decades, there has been explosive growth in our understanding of neuroanatomical, cellular, and molecular mechanisms that mediate central modulation of immune functions through the autonomic nervous system. A major catalyst for growth in this field was the discovery that vagal nerve stimulation (VNS) caused a prominent attenuation of the systemic inflammatory response evoked by endotoxin in experimental animals. This effect was mediated by acetylcholine (ACh) stimulation of nicotinic receptors on splenic macrophages. Hence, the circuit was dubbed the "cholinergic anti-inflammatory pathway". Subsequent work identified the α7 nicotinic ACh receptor (α7nAChR) as the crucial target for attenuation of pro-inflammatory cytokine release from macrophages and dendritic cells. Further investigation made the important discovery that cholinergic T cells within the spleen and not cholinergic nerve cells were the source of ACh that stimulated α7 receptors on splenic macrophages. Given the important role that inflammation plays in numerous disease processes, cholinergic anti-inflammatory mechanisms are under intensive investigation from a basic science perspective and in translational studies of animal models of diseases such as inflammatory bowel disease and rheumatoid arthritis. This basic work has already fostered several clinical trials examining the efficacy of VNS and cholinergic therapeutics in human inflammatory diseases. This review provides an overview of basic and translational aspects of the cholinergic anti-inflammatory response and relevant pharmacology of drugs acting at the α7nAChR.
神经系统和免疫系统在体内有广泛且重叠的分布，这些无处不在的系统的相互作用是神经免疫学领域的核心。在过去的二十年中，我们对介导自主神经系统中枢调节免疫功能的神经解剖学、细胞和分子机制的理解有了爆炸性的增长。这一领域的增长主要得益于一个发现，即迷走神经刺激（VNS）可显著减弱实验动物内毒素引起的全身炎症反应。这种效应是通过乙酰胆碱（ACh）刺激脾巨噬细胞上的烟碱型受体介导的。因此，该通路被称为“胆碱能抗炎通路”。随后的研究确定了α7 烟碱型乙酰胆碱受体（α7nAChR）是抑制巨噬细胞和树突状细胞释放促炎细胞因子的关键靶点。进一步的研究做出了重要发现，即脾内的胆碱能 T 细胞而非胆碱能神经细胞是刺激脾巨噬细胞上α7 受体的 ACh 的来源。鉴于炎症在许多疾病过程中所起的重要作用，从基础科学角度和对炎症性肠病和类风湿关节炎等疾病动物模型的转化研究角度来看，胆碱能抗炎机制都受到了深入研究。这项基础工作已经催生了几项临床试验，以检验 VNS 和胆碱能疗法在人类炎症性疾病中的疗效。本文综述了胆碱能抗炎反应的基础和转化方面以及作用于α7nAChR 的药物的相关药理学。
