Regulation of immune functions by the non-neuronal cholinergic system

简介：人体严格调节局部和全身免疫反应。越来越清楚的是，神经递质乙酰胆碱在这些过程中起着至关重要的作用，尽管这种分子传统上被认为只参与神经功能。要发挥作用，乙酰胆碱必须与16种烟碱乙酰胆碱受体之一结合。这些受体之一，被称为7烟碱乙酰胆碱受体，最为人所知的是当被尼古丁靶向时其抗炎特性。然而，我们有越来越多的证据表明，9烟碱乙酰胆碱受体是免疫调节的关键球员。此外，最近的研究表明，T淋巴细胞可以通过自身合成乙酰胆碱来塑造免疫反应，而乙酰胆碱以前被认为只由神经元产生。我们的初步数据表明，其他非神经元细胞，如骨髓中发现的细胞，也能够产生乙酰胆碱。因此，乙酰胆碱的使用可能比最初想象的更普遍。目的和假设：本研究的主要目的是探索非神经元乙酰胆碱和烟碱乙酰胆碱受体如何控制免疫反应。我们假设，许多免疫细胞本身产生乙酰胆碱与邻近的免疫细胞沟通。然后乙酰胆碱作用于也由各种免疫细胞表达的7和9烟碱乙酰胆碱受体。乙酰胆碱及其受体之间的相互作用激活免疫细胞内的信号并改变它们的功能。意义：该建议将描述乙酰胆碱及其受体在免疫调节中的作用。相关机制的发现对该领域来说是非常新颖的，因此，我们将更好地了解身体如何保持免疫稳定性。

Introduction: The human body tightly regulates local and systemic immune responses. It is becoming increasingly clear that the neurotransmitter acetylcholine plays a vital role in these processes, even though this molecule has been traditionally thought to only be involved in nervous functions. To work, acetylcholine must bind to one of 16 nicotinic acetylcholine receptors. One of these receptors, known as the 7 nicotinic acetylcholine receptor, is best known for its anti-inflammatory properties when targeted by nicotine. However, we have accumulating evidence that the 9 nicotinic acetylcholine receptor is a key player in immune regulation. In addition, recent studies have shown that T lymphocytes can shape immune responses via their own synthesis of acetylcholine, which was previously thought to only be produced by neurons. Our preliminary data show that other non-neuronal cells, such as those found in the bone marrow, are also able to produce ACh. The use of acetylcholine may therefore be more prevalent than originally thought. Objective and hypothesis: The main objective of this proposal is to explore how non-neuronal acetylcholine and nicotinic acetylcholine receptors control immune responses. We hypothesize that many immune cells themselves produce acetylcholine to communicate with neighboring immune cells. Acetylcholine then acts on 7 and 9 nicotinic acetylcholine receptors, also expressed by various immune cells. The interaction between acetylcholine and its receptors activates signals within immune cells and changes the way they function. Significance: This proposal will characterize the role of acetylcholine and its receptors in immune regulation. The discovery of the mechanisms involved would be highly novel to the field, and as such, we will gain a much better understanding of how the body maintains immunological stability.