Abstract
Acetylcholine (ACh) is the classical neurotransmitter in the cholinergic nervous system. However, ACh is now known to regulate various immune cell functions. In fact, T cells, B cells, and macrophages all express components of the cholinergic system, including ACh, muscarinic, and nicotinic ACh receptors (mAChRs and nAChRs), choline acetyltransferase, acetylcholinesterase, and choline transporters. In this review, we will discuss the actions of ACh in the immune system. We will first briefly describe the mechanisms by which ACh is stored in and released from immune cells. We will then address Ca2+ signaling pathways activated via mAChRs and nAChRs on T cells and B cells, highlighting the importance of ACh for the function of T cells, B cells, and macrophages, as well as its impact on innate and acquired (cellular and humoral) immunity. Lastly, we will discuss the effects of two peptide ligands, secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1) and hippocampal cholinergic neurostimulating peptide (HCNP), on cholinergic activity in T cells. Overall, we stress the fact that ACh does not function only as a neurotransmitter; it impacts immunity by exerting diverse effects on immune cells via mAChRs and nAChRs.
Highlights
Acetylcholine (ACh) has long been known as the classical neurotransmitter in the central and peripheral cholinergic nervous systems, molecular biological investigations have revealed its functions in a number of non-neuronal cholinergic systems
Following choline acetyltransferase (ChAT)-catalyzed synthesis in the cholinergic nervous system, ACh is loaded into synaptic vesicles via vesicular ACh transporters (VAChT) and is released from nerve endings by exocytosis triggered by elevation of the intracellular free Ca2+ concentration ([Ca2+]i) induced by nerve impulses
The precise pathway leading to the induction of secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptorrelated peptide-1 (SLURP-1) is not fully understood, these findings suggest Secreted Lymphocyte Antigen-6/Urokinase-Type Plasminogen Activator Receptor-Related Peptide (SLURP)-1 should be considered for the development of new treatment approaches for cancer
Summary
Acetylcholine (ACh) has long been known as the classical neurotransmitter in the central and peripheral cholinergic nervous systems, molecular biological investigations have revealed its functions in a number of non-neuronal cholinergic systems. It is known that non-neuronal cholinergic systems present in various tissues and organs are involved in diverse physiological and pathophysiological processes, including immune and inflammatory responses, wound healing, cancer development and progression, and cardiovascular, respiratory, digestive, and orthopedic diseases (for further details, please see the reviews [1,2,3]). In 2019, the 5th international symposium on non-neuronal ACh was held in Long Beach, CA, USA (27–29 September); presented were results from numerous ongoing studies on the non-neuronal cholinergic system in the context of diverse cells and organs (please see the proceedings “The 5th International Symposium on Non-neuronal Acetylcholine” [4]). Given the recent publication of extensive and comprehensive reviews on the “cholinergic anti-inflammatory pathway” [2,3,5], in this review we will focus mainly on the cholinergic system in immune cells
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