Cholinergic System and Its Therapeutic Importance in Inflammation and Autoimmunity

Abstract

Neurological and immunological signals constitute an extensive regulatory network in our body that maintains physiology and homeostasis. The cholinergic system plays a significant role in neuroimmune communication, transmitting information regarding the peripheral immune status to the central nervous system (CNS) and vice versa. The cholinergic system includes the neurotransmitter\ molecule, acetylcholine (ACh), cholinergic receptors (AChRs), choline acetyltransferase (ChAT) enzyme, and acetylcholinesterase (AChE) enzyme. These molecules are involved in regulating immune response and playing a crucial role in maintaining homeostasis. Most innate and adaptive immune cells respond to neuronal inputs by releasing or expressing these molecules on their surfaces. Dysregulation of this neuroimmune communication may lead to several inflammatory and autoimmune diseases. Several agonists, antagonists, and inhibitors have been developed to target the cholinergic system to control inflammation in different tissues. This review discusses how various molecules of the neuronal and non-neuronal cholinergic system (NNCS) interact with the immune cells. What are the agonists and antagonists that alter the cholinergic system, and how are these molecules modulate inflammation and immunity. Understanding the various functions of pharmacological molecules could help in designing better strategies to control inflammation and autoimmunity.

Keywords: choline acetyltransferase (ChAT); cholinergic system (CS); muscarinic acetylcholine receptors (mAChR); neuroimmunology; neurotransmitters; nicotinic acetylcholine receptors (nAChR).

Figure 1

Synthesis and degradation of ACh. ACh is synthesized from Acetyl-S-CoA and choline by the choline acetyltransferase (ChAT) enzyme in the cytoplasm. ACh is secreted out immediately after synthesis in non-immune cells but stored in a specialized vesicle in neuronal cells secreted at presynaptic neurons after activation. Release of ACh requires an influx of Ca2+ ion in the cells followed by docking of ACh-containing vesicle docking at membrane and fusion and release of neurotransmitter into the synaptic cleft via a process known as exocytosis. ACh binds via the autocrine or paracrine mechanism to nicotinic acetylcholine receptors (nAChRs) or muscarinic acetylcholine receptors (mAChRs) on post-synaptic neurons or immune cells. Acetylcholinesterase (AChE) present on the membrane can degrade ACh into choline and acetic acid. Extracellular choline formed is transported into the cells by choline transporters.

Figure 2

Structure of human α3β4-nAChR complexes with nicotine. The human nAChR complex with α3β4 nicotine acetylcholine receptor (Protein data bank Id: 6PV7) is displayed using the online iCn3D software. The structure is composed of two α3 chains and three β4 chains. The Fab fragments of the antibody used for stabilization of the sample are shown at the top. Nicotine is shown in balls and sticks. Red and blue discs represent the plasma membrane. The thick arrow depicts the regulation of the movement of ions by the central pore.

Figure 3

Structural interaction of M₁ mAChR with the G protein-coupled receptor. The human muscarinic acetylcholine receptor 1G11 protein complex (Protein data bank Id: 6OIJ) structure (3.3 Å resolution) is displayed using the online iCn3D software. M₁ mAChR interacts with G-proteins α11 and γ2-β1. The scFV16 nanobody used for stabilizing the structure is also shown. The allosteric ligand is shown in the ball and stick. Red and blue discs represent the plasma membrane.