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.

Introduction

The complex bi-directional neuroimmune communication maintains each organ’s physiological balance and functions in the body. The central and peripheral neuronal circuits, immune cells and cytokines, neuro-endocrine hormonal systems, gut microbiota and their metabolites, and the blood-brain and intestinal mucosal barriers are important players throughout this regulatory network. Any disturbance in these systems alters the delicate balance between health and disease (1). The physiological mechanism of cross-talk within the neural network and reticuloendothelial system that regulates immune response, metabolism, and a vast array of pivotal functions constitute the inflammatory reflex (IR). The parasympathetic afferent and efferent arms of the Vagus nerve (VN) serve as a control center that connects impulses between the brain and internal organs (2). The afferent fibers of the VN have innervation in the reticuloendothelial system and major organs of the body. It is activated by low cytokines or endotoxins present in the tissues and communicates via neuronal signals sent to the poor cytokine milieu of the central nervous system (CNS) (3).

ACh has also been detected in cells of non-neural origins and microbes. It is vastly found in cardiomyocytes, the entire gastrointestinal (GI) tract, bladder urothelial cells, and various human leukemic cells, demonstrating its diverse function within an organism. The non-neuronal cholinergic system (NNCS) is made up of neurotransmitter acetylcholine, its synthesizing and degrading enzymes, transporters, and receptors within epithelial cells in airways, intestine, skin, urothelium, vagina, placenta, cornea, granulosa cells, endothelial cells, immune cells and mesenchymal cells (4). Signal transduction in keratinocytes, lymphocyte proliferation and differentiation, regulation of cytoskeleton of epithelial cells, differentiation and migration of cells in the epidermis for wound healing, ciliary activities, and regulation of the permeability in the epithelial lining of airways in an autocrine/paracrine manner (5). The details of neuronal origin cholinergic systems, their components, and signaling in the tissues have been discussed earlier (6, 7).

In this review, several immune cells that express components of NNCS and respond to neurotransmitters, specific agonists, and antagonists and their contribution to inflammation and autoimmunity are discussed. We further explored the different cholinergic agonists, antagonists, and AChE inhibitors (AChEI) that modulate the immune system and their effect on the differentiation and function of various immune cells.

Components of the Non-Neuronal Cholinergic System (NNCS) in Immunity

Acetylcholine (ACh)

The cholinergic system, which is found in both neuronal and non-neuronal cells, forms a network that performs various complex functions in the body. The ChAT enzyme synthesizes ACh from the precursor molecules, choline (8). The majority of choline is formed by the degradation of lipid, especially lecithin, and hydrolysis of acetylcholine (9). Acetyl-coenzyme A (Acetyl-CoA), produced by mitochondria, is used for the esterification of choline by the cytoplasmic enzyme ChAT in the parasympathetic nervous system and motor neurons (Figure 1). In addition to the VN, T cells, B cells, dendritic cells (DCs), and macrophages in the follicular and marginal zones of the spleen are other major sources of ACh (10). Immune cells have the machinery to synthesize ACh and directly release it into the bloodstream. In contrast, neuronal cells store ACh after synthesis in a specialized neurosecretory vesicle and release it via exocytosis at specialized synaptic clefts (11).

Figure 1

The relative concentration of ACh in humans is found to be 8.66 ± 1.02 pmol/ml in the blood and 3.12 ± 0.36 pmol/ml in plasma (12). Ach is also produced by gut microbes like Lactobacillus plantarum (13). Physiological levels of ACh present in the bloodstream affect immune cells in the lymphoid tissues and those that are migrating to the site of inflammation in an autocrine and paracrine manner. Recent studies have correlated lower levels of ACh in chronic inflammatory neurodegenerative diseases like Alzheimer’s disease (AD), vascular dementia (VD), and multiple sclerosis (MS) (14–16). The elevated ACh level is also linked to inflammatory diseases like atopic dermatitis, chronic obstructive pulmonary disease (COPD), and periodontal disease (17–19). Patients with acute ischemic stroke had higher levels of lymphocyte-derived-ACh, which was linked to an increase in post-stroke infection and mortality (20). The diverse ways in which ACh binds to and activates different types of receptors on the surface of various cells and tissues explain its differential outcome and functions within an organism.

Choline Acetyltransferase (ChAT) Enzyme

ChAT is responsible for the biosynthesis of ACh. The ACh content in cells is proportional to the expression of ChAT within the cells (21). This enzyme is synthesized in the perikaryon of cholinergic neurons and is under the control of multiple regulatory elements (22). The enzyme occurs in both soluble and membrane-bound forms and is transcribed from various ChAT mRNA species that share identical coding regions but differ in the 5’-noncoding regions (23). R, N0, N1, N2, and M-types are some of the ChAT mRNA species that have been identified (24). N1 and N2 type mRNA transcript of ChAT is expressed by T cells, thus differing from the R type in CNS (25). In a murine model, ChAT mRNA is constitutively expressed in T and B cells and mononuclear lymphocytes isolated from the renal vasculature (21). Upon immunological activation, peritoneal macrophages and bone marrow-derived DCs increase ChAT transcription compared to cells in the resting stages (26). ChAT mRNA expression is also detected in human leukemic T cell lines, human peripheral blood T cell and B cells, human lung and alveolar macrophages, and monocytes (27–29). COPD patients’ neutrophils were observed to have over-expression of ChAT. In contrast, epithelial cells of ulcerative colitis patients displayed downregulation of ChAT, indicating, ChAT has differential involvement in different diseases affecting epithelial linings and smooth muscles (30, 31). Several natural and synthetic compounds have been identified as having ChAT stimulatory or inhibitory functions, consequently affecting the immune cells. The summary of the effect of ChAT activators and inhibitors is listed in Table 1.

Cholinesterase (ChE) and Cholinesterase Inhibitors (ChEI)

The degradation of ACh into choline and acetate ions is regulated by acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.7) enzymes, as shown in Figure 1. AChE is a 537-amino-acid protein that functions as a primary serine hydrolase. It has a recovery time of around 100 microseconds and can hydrolyze 6 X 10⁵ ACh molecules per minute (63). BChE is a nonspecific serine hydrolase capable of hydrolyzing broad choline-based esters, thus serving as a co-regulator of cholinergic transmission (64). With a half-life of 20 to 60 days, AChE is predominantly found in the neuromuscular junction (NMJ), plasma, liver, and erythrocytes, while BChE is primarily found in the liver and blood plasma, with a reduced half-life of 10 to 14 days in these tissues (65, 66). The cholinergic system-specific catalytic activity of AChE/BChE degrades signal transmission by ACh and determines one’s cholinergic status (CS) (67). Ubiquitous expression of AChE is found within mouse lymphocytes, DCs, and macrophages (68).

In two independent studies, serum AChE levels and CS were substantially higher in patients with irritable bowel syndrome (IBS), whereas CS was significantly lower in IBD patients (69, 70). AChE immunoreactivity was also higher in cirrhotic livers, suggesting a connection between CS dysregulation and GI diseases (71). The possible link of reduced AChE and BChE enzyme activity to proinflammatory processes through hydrolysis of ACh was evident in diseases like MS and AD (72, 73). ChE activity, in turn, can be modulated by ChE inhibitors (AChEIs and BChEIs), thereby increasing ACh levels in the body. The pharmacokinetic properties of ChEIs are thus exploited for the treatment of neurodegenerative and inflammatory diseases like myasthenia gravis (MG) and AD (74). Some ChEIs, such as donepezil, galantamine, and rivastigmine, are currently being used to treat AD (75, 76). Some of the synthetic molecules that enhance or inhibit ChE and affect cholinergic transmission are listed in Table 2. While many of these molecules have been studied in the context of neurological diseases, how they modulate inflammation and autoimmunity is still under investigation.

Choline Transporter (ChT) and Vesicular Acetylcholine Transporter (VAChT)

ChTs are expressed on the cell membranes of cholinergic neurons in presynaptic terminals and regulate the ACh reservoirs during autonomic, cognitive, and motor functions (111). This membrane protein helps transport the precursor molecule choline into the neurons for the synthesis of ACh (111). ChTs are predominantly found on the plasma membrane of microvascular cells. They are also highly expressed on the mitochondrial membrane, where they are involved in choline oxidation upon absorption. Bone marrow-derived macrophages treated with lipopolysaccharide (LPS) show increased transcript and protein expression of the choline transporter-like protein-1 (CTL1) (112). The human leukemic T-cell line expresses CHT1 mRNA and mediates choline uptake in T cells (113). Activation of protein kinase C causes inhibition of CTL1 in macrophages, thereby causing altered cytokine secretion (114). The distribution of ChT on different immune cells and its importance in the specific tissue microenvironment in controlling inflammation and immunity need to be further investigated.

ACh is packaged into the secretory vesicles by a specific transporter protein VAChT using an exchange of protons (H⁺) (115). Most cholinergic neurons in the brain, spinal cord, and NMJ with skeleton muscle express VAChT (116). Alteration of VAChT expression has consequences on the concentration of acetylcholine loaded in the secretory vehicle, thus indirectly maintaining the neurotransmitter release. Dysregulation of VAChT has been reported in several diseases like AD, Epilepsy, and Sepsis (117–119). VAChT knockdown (VAChT-KD) mice, upon LPS challenge, show increased susceptibility to inflammation and greater mortality. LPS challenge increases the levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) in the spleen, brain (120). Human melanocytes, keratinocytes, and alpha-cells also express non-neuronal VAChT, thereby regulating the acetylcholine release and cholinergic activity (121, 122). The expression and function of VAChT on immune cells are still unclear and thus have potential physiological consequences in the peripheral immune response.

Acetylcholine Receptors (AChRs)

The diversified role of ACh is governed by different types of receptors, known as cholinergic receptors (AChRs), which are classified according to their affinity for various chemical ligands (123).

Nicotinic Acetylcholine Receptors (nAChRs)

These receptors respond to the ligand, nicotine. These ligand-gated ion channels are composed of four distinct subunits (α1–10, β1–4, γ, and δ) bound in different stoichiometric ratios around a central pore with the help of ϵ subunits (Figure 2). These receptors exist as homomers (with all subunits of one type), such as (α7)₅, or as heteromers with at least one α and one β subunit among the five subunits that are combined in various combinations, such as (α4)₃(β2)₂, (α4)₂(β2)₃, (α3)₂(β4)₃, α4α6β3(β2)₂ (124). The structure of the human α3β4-nAChR complex, solved using cryoelectron microscopy (125), is shown in Figure 2. This structure shows a central channel formed by different subunits of nAChRs. The channels help move ions from the extracellular environment to the cytoplasmic side or vice versa in the cells after stimulation with specific ligands (Figure 2). The α3β4-nAChR subtype is located in the autonomic ganglia and adrenal glands, which forms the main relay between the central and peripheral nervous systems in the hypothalamic-pituitary-adrenal axis (HPA) axis upon activation (126). Diverse nAChR subtypes confer differential selectivity for nicotinic drugs in the central and peripheral nervous system, muscles, and many other tissues (127). The ligand binds to the specific site of the receptor leading to the triggering of all subunits of nAChR to change conformation, resulting in the opening of a non-selective cation channel, which then regulates the movement of ions (128).

Figure 2

In the immune system, nAChRs are known to regulate inflammatory processes (129). Pathological causes in acquired neurodegenerative diseases, such as autoimmune ganglionopathy, autoimmune encephalitis, and MG, are caused by an autoimmune reaction against nAChRs in the NMJ (130–132). Non-neuronal nAChRs are also involved in the pathogenesis of palmoplantar pustulosis, psoriasis, and rheumatic diseases (133–135). Overexpression of nAChR in gastric, colorectal, pancreatic, liver, lungs, and breast tumors appears to regulate cancer cell processes such as proliferation, apoptosis, angiogenesis epithelial-mesenchymal transformation (136, 137). Several of the nAChR agonists and antagonists are known to work in a receptor-specific and selective manner. Some of the agonists and antagonists are listed in Tables 3 and 4. Treatment with these ligands and their effect on immune cells is not very well studied and needs detailed investigation.

Muscarinic Acetylcholine Receptors (mAChRs)

These are metabotropic receptors consisting of seven transmembrane subunit G protein-coupled receptors (GPCRs) that respond to ACh and muscarine (248). M₁ to M₅ mAChR subtypes share 64 to 68 percent sequence identity and 82 to 92 percent sequence similarity, indicating that they have a high degree of sequence homology. Their G-protein coupling preferences and physiological functions, however, are different. mAChRs have been separated into two groups based on their functional coupling. The M₁ mAChR, M₃ mAChR, and M5 mAChR are coupled to G_q/11 proteins, which mediate the activation of phospholipase C (PLC) activity (249). The M₂ mAChR and M₄ mAChR are coupled to the G_i/o protein, which mediates inhibition of adenylate cyclase (AC) and thus causes a decrease in cyclic adenosine monophosphate (cAMP) (248). Based on the physiology and distribution of the individual receptor, mAChRs can trigger different signal transduction pathways in the cells in a tissue-specific manner. Recently, the structures of the human M₁ mAChR and M₂ mAChR2 with G-protein complexes were published (250). The structure visualization of human M₁ mAChR with the G-protein complex is shown in Figure 3. mAChRs have an extracellular ligand-binding domain and a transmembrane and intracellular signaling domain. The intracellular domain interacts with G proteins and other signaling molecules and helps intracellular signaling (Figure 3). mAChRs are abundant in the hippocampus, cortex, thalamus, gastric and salivary glands, smooth muscle, and cardiac tissue, each having a specific downstream signaling cascade. Thus, the structural differences, ligand specificity, and functioning mechanism help understand each receptor’s roles within specific tissues. In the murine endotoxemia model, muscarinic receptor-mediated cholinergic signaling in the forebrain regulates peripheral immune function and inflammation to suppress serum TNF-α levels (251). Conversely, the major cause for the pathogenesis of autoimmune Sjögren’s syndrome is the production of auto-antibodies against the M₃ mAChR (252). Autoantibodies against muscarinic receptors also triggered chronic immune activation in patients with chronic fatigue syndrome and periodontitis (253, 254). Patients with airway inflammatory infections/allergic rhinitis had increased expression of M₃ mAChR mRNA and protein (255). However, the specific patterns of mAChR subunit distribution in tissues and expression in particular immune cell types are not well defined. Some of the selective mAChR agonists and antagonists are listed in Tables 3 and 4, respectively. Given the diverse distribution of mAChRs in different immune cells, the mechanism by which selective ligands alter specific immune cells in the tissue microenvironment during inflammation and immunity needs detailed investigation.

Figure 3

The Role Played by the Cholinergic System in Various Immune Cells

The neuronal and lymphoid cholinergic system evokes various downstream functional and biochemical effects through AChRs present on immune cells. The importance of different components of the complex cholinergic system in different immune cells is discussed below-

Role in T Cells

T cells and their effector and regulatory function play an important role in inflammation and autoimmunity (256, 257). Some splenic and intestinal T cell subsets have been found to express functional ChAT and produce ACh (ChAT⁺ T cells) (21, 258). Most of these T cell subsets are found in the vicinity of catecholamine splenic nerve fibers forming a cholinergic non-neuronal reservoir (259). The ACh produced in the microenvironment activates α7-nAChR on T cells and facilitates the activation and proliferation of T cells (260). In vitro administrations of nicotine or ACh in a micromolar range inhibits DC mediated-T cell proliferation and differentiation, as well as reduce CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression and diminished maturation in T cells (261, 262). Endogenously released ACh in human leukemic T cell upregulates several Ca²⁺-permeable ACh-gated ion channels. Nicotine also impairs antigen receptor-mediated signal transduction in lymphocytes and causes T cell anergy by arresting cells in the G0/G1 phase (263). It is also known to alter the expression of co-stimulatory and adhesion molecules (such as ICAM and CD44) on immune cells and suppress the production of inflammatory cytokines (TNF-α, IFN-γ, and IL-6) (264). Nicotine binds to various forms of nAChR on T cells with variable affinity and mediates the apparently paradoxical effects of fostering cell survival while also causing apoptosis by inducing expression of FasL and survivin gene (265). The receptors, α7-nAChRs and α4-nAChR are predominantly known to be involved in CD4⁺ T cell proliferation and function (266, 267). The α7-nAChR antagonist, α-bungarotoxin (α-BTX), and methyllycaconitine (MLA) show an increased proliferative response to the T cell mitogen, phytohemagglutinin (PHA) (268). Activation of the α7-nAChR by nicotine in experimental autoimmune encephalomyelitis (EAE) mice model ameliorate clinal symptoms by directing naive CD4⁺ T cells towards the IL-4-producing Th2 phenotype and subsequently leads to decreased production of Th1 cytokines (such as TNF-α, IFN-γ, IL-2) and Th17 cytokines (such as IL-17, IL-17F, IL-21, and IL-22). However, activation of α7-nAChR with agonist does not affect the differentiation of Th17 cells (269). α7-nAChR activation with nicotine in human PBMC and CD4⁺ T cells results in a similar reduction of IL-17 production, suggesting that it has an anti-inflammatory property (270). Nicotine-induced activation of α7-nAChRs also increases the suppressive function of CD4⁺CD25⁺Tregs/CD4⁺CD25⁻ T-cell by up-regulation of CTLA-4 as well as Foxp3 expression and decreased IL-2 secretion (271). These studies suggest that nAChRs activation can modulate the function of various subsets of CD4⁺ T cells.

In humans, all five subtypes of mAChRs are known to be expressed on lymphocytes. However, each receptor’s expression pattern differs among different cell types in an individual (29). PHA is known to increase M₅ mAChR mRNA expression in vitro, while lymphocytes stimulated with phorbol 12-myristate 13-acetate (PMA), a protein kinase C activator, plus ionomycin, a calcium ionophore, increase M₃ and M₅ mAChR mRNA expression, demonstrating that differential expression of mAChR is caused by different immunological stimulations (272). Activation of the M₃ mAChR using methacholine on CD4⁺ T cells isolated from airway inflammatory infections/allergic rhinitis patients leads to increased production of IL-4 and TNF-α (255). Treatment of Jurkat cell lines with the mAChR agonist, oxotremorine (OXO-M), increases the expression of IL-2 receptors on lymphocytes and enhances the PMA-induced IL-2 secretion (273). Interestingly, it was found that arecoline, a non-selective muscarinic agonist improves cognitive function and memory in AD (274). Chronic treatment with arecoline leads to a reduction in the size of the spleen, thymus, and mesenteric lymph nodes, as compared to untreated control mice. In-vitro arecoline treatment was shown to reduce lymphocyte proliferation and IL-2 production (275). M₃ mAChR knockout (M3^-/-) mice were reported to have trouble in clearing bacterial and helminth infections. The absence of M₃ mAChR also led to delayed expulsion of Nippostrongylus brasiliensis due to inhibition of smooth muscle contraction, a reduction in the activation of CD4⁺ T cells, and lower levels of expression of IL-4 and IL-13. The activation of the M₃ mAChR, specifically with ACh on activated T cells, increases IL-13 and IFN-γ cytokine production (276). The distribution of the M₁-M₅ mAChR on each subset of CD4⁺ T cells in humans and mice has not been systemically studied and is therefore open for further investigation.

Role in B Cells

Mouse B cells are known to express α4, α5, α7, β2, and β4 subunits of nAChR, with the expression of different subunits being regulated at the various stages of B cell maturation (277). At the primary level, nAChRs are required for the development and survival of B lymphocytes within the primary lymphoid tissues and spleen. α4 and β2 knockout mice have reduced B cell populations, underscoring their critical role in regulating lymphocyte survival (278). The CD19⁺B220⁺IgM⁺ B lymphocytes mainly expressed α7, α4, and β2 subunits of nAChRs. Mice deficient in these subunits of nAChRs showed reduced amounts of serum IgG, while β2^−/− mice had a reduced number of IgG-producing cells in the spleen. However, the IgG response to horse cytochrome c in α4 and β2 knockouts was stronger than in wild-type (WT) mice, with the β2^−/− mice having high cytochrome c-specific antibodies after immunization (279). Also, α7-nAChR influences IgM antibody production but not IgM to IgG class switching (280). α7-nAChR is constitutively expressed on CD5⁺CD1d⁺ regulatory B lymphocytes, which increases with the activation of B lymphocytes. Inhibiting α7-nAChR with methyllicaconitine inhibits CD40-mediated B lymphocyte proliferation (281). α4β2-nAChR, α7-nAChR, and α9α10-nAChR on B lymphocytes are differentially involved in B cell-mediated immune cell interactions. α7 and α9(α10) subunits of nAChRs are linked to CD40-mediated B cell proliferation, while the α4β2-nAChR is linked to IgM antibody production (151). However, the initial levels of IgM in WT and knockout mice were similar. The OVA-antigen-specific IgG1 levels in mice were significantly lower, suggesting that mAChRs are not required for antibody production but are involved in immunoglobulin class switching (282). M₁ mAChR knockout () mice show increased splenic noradrenaline production and a decrease in the number of IgG-producing B cells (283). M₃ mAChR in B cells show an increase in calcium signaling and c-Fos gene expression, thereby affecting several downstream signaling pathways (284). However, an autoantibody against the M₃ mAChR has been reported in the immunopathogenesis of Sjögren’s syndrome and correlates with a significant risk of developing B cell lymphoma (285). Together, these studies suggest that AChRs contribute to mounting an effective humoral response. A detailed investigation of cholinergic systems’ expression in the different developmental and differentiation stages of B cells needs to be investigated, and its clinical importance in the inflammatory disease yet to be established.

Role in Dendritic Cells (DCs)

Nicotine impairs the capability of DCs to capture antigens and reduces the responsiveness of DCs to maturation stimuli. The nicotine-treated DCs fail to produce IL-12, IL-1β, IL-10, and TNF-α and thus unable to induce APC-dependent T cell responses and Th1-cell polarization. DCs exposed to nicotine tend to polarize CD4⁺ T cells towards the Th2 phenotype. These show increased expression of OX40L and significantly high amounts of IL‐4, IL‐5, and IL‐13 (261, 286). CD205⁺ DCs express mRNA encoding secreted lymphocyte antigen-6/Urokinase-type plasminogen activator receptor-related peptide (SLURP)-1, an endogenous α7-nAChR allosteric ligand that stimulates DCs to produce ACh in an autocrine manner (260). Treatment with GTS-21, an α7-AChR agonist, showed a robust anti-inflammatory action during collagen-induced arthritis (CIA) in DBA/1 mice by modulating DCs. GTS-21 treatment down-regulated CD80 and MHC II expression on the surface of DCs, leading to suppression of its infiltrating capacity and differentiation. These inhibitory effects were successfully reversed by the α7-nAChR antagonist, methyllycaconitine (287, 288). Treatment of DCs with ACh also resulted in the upregulation of the macrophage‐derived chemokine (CCL22) in the thymus and the activation‐regulated chemokine (CCL17). CCL22 and CCL17 help in the recruitment of Th2 cells at the site of inflammation (289). In both mice and humans, DCs treated with nicotine utilize upregulation of notch ligands and nuclear receptor peroxisome proliferator-activated receptors γ (PPAR γ) to modulate the Th1/Th2 balance in favor of Th2 lineage (290). Activation of nAChRs on immature DCs (imDCs) has also been shown to have anti-tumorigenic effects. Activation of nAChR promotes the expression of co-stimulatory molecules CD80/CD86 and 4-1BBL on imDCs, thereby increasing their ability to stimulate T-cell proliferation. Transfer of nicotine-treated imDCs has been shown to reduce tumor growth by generating an effective cytotoxic T cell response in the tumor microenvironment (291).

DCs have been found to express the M₃ mAChR, M₄ mAChR, M₅ mAChR, ChAT, and AChE (289). Methacholine, a synthetic choline ester, and a non-selective mAChR agonist were shown to increase expression of the OX40L on DCs, which helps in the interaction co-stimulation with T cells (255). Cholinergic activation using the M₁ mAChR-specific agonist, McN-A-343, in colitis was found to decrease IFN-γ, IL-17, IL-12p70, and IL-23 in the splenic CD11c⁺ DCs (181). These studies suggest that AChRs affect the immune response by altering innate immune cells like DCs. Further detailed molecular mechanism of cholinergic receptor signaling in the differentiation and function of DCs under different inflammatory conditions and tissues needs to be investigated.

Role in Macrophages

The intracellular signaling of alveolar macrophages is mediated by α9, α10, and β2-nAChR. Macrophage populations previously exposed to nicotine show a lower rise in ATP-induced intracellular Ca²⁺ release, which is independent of STAT3 phosphorylation (292). The α7-nAChR on macrophages is vastly sensitive to ACh released by the ChAT⁺ T cells, and its interaction with ACh leads to reduced production and release of proinflammatory cytokines. Antigen-stimulated spleen cells from α7 knockout mice produce significantly higher amounts of TNF-α, IL-6, and IFN-γ than splenocytes from WT mice (264). Vagus nerve stimulation (VNS) for a duration of 0.1–60s in WT mice modulates cytokine release from macrophages via the α7-nAChR receptor. However, the α7 subunit deficiency rendered the VN ineffective in inhibiting TNF-α release (293). Priming macrophages with a cognate ligand for α7-nAChRs results in a pharmacological inhibition of AC which in turn increases the cAMP levels in the cells. Thus, activation of α7-nAChR in macrophages promotes expression and phosphorylation of c-FOS and CREB, required for a sustained decrease in the endotoxin-induced release of TNF-α (294). In LPS-stimulated human macrophages, ACh-induced activation diminishes pro-inflammatory cytokines like TNF-α, IL-1β, IL-6, and IL-18, but not the anti-inflammatory cytokine, IL-10 (295). VNS causes activation of nAChRs on macrophages, thus hampering their activation via the JAK2-STAT3 signaling pathway. nAChR antagonist treatment of macrophages causes enhanced expression of JAK2 and STAT3, which negatively regulate metalloproteinase 9 (MMP-9) production and inhibit macrophage migration (296, 297). It was found that nicotine treatment led to overexpression of IL-1 receptor-associated kinase M (IRAK-M), a negative regulator of TLR4 signaling, via α7-nAChRs. Upregulation of IRAK-M expression is required for the anti-inflammatory effect of nicotine on LPS-induced TNF-α production by peritoneal macrophages (298). In these macrophages, nicotine treatment significantly lowered ATP-induced intracellular Ca²⁺ signaling via β2-nAChR only (299, 300).

The muscarinic agonist, carbachol, causes a moderate enhancement in phagocytosis of zymosan particles by primary peritoneal macrophages (301). Depending on the local microenvironment, several mAChR subtypes were reported on differentiated resident macrophages. Activation of M₁–M₃ mAChR causes tumor macrophages to proliferate mainly by activating the arginase pathway, producing high prostaglandin E2, and promoting potent angiogenesis. Likewise, in normal macrophages, activation of M1–M₂ mAChR- triggers protein kinase C activity and induces moderate prostaglandin E₂ liberation for proliferation (302).

Role in Mast Cells

Treatment of patients suffering from allergic diseases with nicotine leads to suppressing the production of Th2 cytokines and cysteinyl leukotriene LTC₄. Crosslinking of the high-affinity receptor of IgE on mast cells causes its activation. Upon activation, mast cells at the early phase release preformed inflammatory mediators, and in the late phase, they synthesize and secrete cytokines/chemokines and leukotrienes. Treatment with low concentrations of nicotine leads to suppressing the late-phase, but not of the degranulation response. α7/α9-nAChR antagonists, methyllycaconitine, and alpha-bungarotoxin, successfully reverses nicotine’s suppressive effect on the late-phase response (303). mAChRs have also been characterized in human mast cells as tissue-based mediators that regulate histamine release and control hypersensitivity (304, 305). Upon treatment with nicotine, the human basophil cell line, KU-812, and the human mast cell line, HMC-1, are known to express nAChRs, thereby corroborating ACh expression reports by several cell types outside the neuromuscular system (306).

Atropine, a non-selective mAChR antagonist, has been shown to reduce the permeability of colon tissue in patients with ulcerative colitis and also further diminish histamine release and disrupt the interactions between mast cells corticotropin-releasing factor (CRF), and eosinophils in the mucosal barrier (307). OXO-M, a stable agonist of mAChR, and physostigmine, an AChE inhibitor, suppress histamine release (308). Methoctramine, an M₂ mAChR antagonist, has been reported to activate phosphoinositide breakdown at high concentrations via pertussis toxin-sensitive G proteins, with subsequent histamine (309). M₁ mAChR signaling modulates phosphoinositide (PI) 3-kinases, which are critical regulators of mast cell degranulation (310). Mast cell degranulation requires IgE signaling and receptor-mediated calcium mobilization (311). The lethal toxin of Clostridium sordellii is known to inhibit Rac, thereby disrupting calcium turnover and blocking M₁-mediated exocytosis in RBL 2H3-hm1 mast cells (312). Together, these studies suggest that AChRs can alter mast cell function and contribute to the pathogenesis of mast cell-mediated diseases.

Role in Neutrophils

The mRNA and protein expression of several nAChR subunits, such as α1, α3, α4, α7, β2, and β4, are also reported in human polymorphonuclear neutrophils (PMN). The α7, α4β2, and α3β4 subunits of nAChR on PMNs have been shown to have regulatory roles in their maturation at the site of inflammation (313). During inflammation, cell surface adhesion molecules play an integral role in the migration of neutrophils from lymphoid organs to the peripheral inflammatory site. nAChRs are known to regulate the expression of the cell surface protein, CD11b, on the surface of neutrophils. Nicotine administration and VNS significantly reduce surface expression of CD11b on neutrophils via suppression of F-actin polymerization, thereby reducing neutrophil attachment to the endothelium surface and transmigration to inflamed sites caused by microbial infection (314).

In mice, treatment with the non-selective cholinergic antagonist, atropine, led to an increase in the neutrophil population and increased serum corticosterone (CORT) concentrations in treated mice compared to WT mice (315). Neutrophil chemotactic activity is regulated by acetylcholine-mediated IL-8 release from epithelial cells via mAChR. ACh significantly stimulates the ERK1/2 and NFkB pathways, leading to an increase in chemotaxis by neutrophils, which can be reversed by tiotropium, an antagonist of the M₃ mAChR (316). The M₃ mAChR takes active participation in triggering cell death and contributes to the pathophysiology observed in several autoimmune diseases like vasculitic inflammation and thrombosis. The stimulation of M₃ receptors on neutrophils induces neutrophil extracellular trap formation via the Akt, RAF/MEK/ERK pathway, ROS induction, and peptidyl arginine deiminase activation (317). Blocking the M3 mAChR reduces the proinflammatory effect of ACh on smooth muscles, as well as epithelial and endothelial cells. M₃ mAChR knockout mice show altered neutrophil recruitment due to the downregulation of cell adhesion molecules like fibrinogen-α and CD177 (318). Sputum samples in healthy smokers and chronic obstructive pulmonary disease (COPD) patients have been shown to have increased TGF-β1 and ACh concentrations, consequently increasing neutrophil adhesion to epithelial cells. TGF-β1 depletion significantly reduces M₃ mAChR and ChAT expression on epithelial cells, thereby establishing autocrine/paracrine feedback during neutrophilic inflammation (319). It is also noticed that during airway hyper-responsiveness due to infections, TNF-α production by neutrophils negatively regulates the M₂ mAChR, causing vagally-mediated bronchoconstriction (320).

Role in Natural Killer (NK) Cells

NK cells play a very important role in several inflammatory and chronic diseases (321). Human NK cells show the complete cholinergic machinery expression, including ChAT, VAChT, AChE, and ChT1 (322). Upon acute inflammation, ChAT⁺ NK cells upregulate the synthesis of ACh to stimulate monocytes, modulate cytokine expression in the tissue microenvironment, and reduce inflammatory damages (322). Highly purified NK cells have been reported to express α4, α5, α6, β2, and β3 subunits of nAChR receptor (323). Under inflammatory disease conditions, NK cells increase the production of ACh by upregulation of ChAT enzymes. ChAT expression also increases along with the maturation of NK cells. Adoptive transfer of ChAT-expressing NK cells (ChAT⁺ NK cells) into the cerebral ventricles of CX3CR1^−/− mice reduces inflammation and autoimmune responses in the experimental autoimmune encephalomyelitis (EAE) model (322). ChAT⁺ NK cells have been shown to successfully reduce the infiltration of CCR2⁺Ly6C^hi monocytes and lower the secretion of proinflammatory cytokines. The anti-inflammatory effect of NK cells is mediated via α7-nAChRs. NK stimulation with cytokines (IL-12, IL-18, and IL-15) increases the transcription and translation of α7-nAChR (322). Activation of α7-nAChR in NK cells decreases their NK group 2D member (NKG2D)-dependent cell-mediated cytotoxicity and IFN-γ production, thereby showing anti-inflammatory properties during inflammation (158). β2-nAChR modulates NK cell functions via NF-κB-induced transcriptional activity in NK cells (323). Aberrant functioning of NK cells is the major cause of tumorigenesis and multiple cancers. It has been reported that single nucleotide polymorphisms (SNPs) of mAChR in natural killer cells result in dysregulation of Ca²⁺ signaling and reduced NK cell cytotoxic activity, leading to the pathophysiology observed in myalgic encephalomyelitis/chronic fatigue syndrome (324). The cytotoxicity of NK cells towards YAC-1 target cells was inhibited by the addition of ACh, suggesting that AChRs on NK cells control the cytotoxic function of NK cells. Furthermore, pilocarpine, an agonist of the mAChR, showed a similar effect on the cytotoxicity of NK cells when atropine was used to block the inhibitory effect of ACh (325). Together, these studies suggest that AChRs can affect the NK cell function in different inflammatory diseases.

Role in Eosinophils

Human peripheral blood eosinophils express the M₃-M₅ mAChRs, and activation of these mAChRs has an inhibitory effect on the activation of these cells (307, 326). Eosinophils play an important role in allergic disorders such as rhinitis, atopic dermatitis, and asthma. In ulcerative colitis, the cholinergic system in eosinophils at the mucosal barrier may contribute to mucosal inflammation (307). However, the role of mAChRs in eosinophils need detailed investigation.

Pre-Clinical and Clinical Importance of the Cholinergic System

The vagal efferent nerves originate at the medulla and innervate the GI tract, connecting it to the ENS. This gut-brain axis is known to regulate GI motility and secretion via vagal efferent fibers, which form cholinergic synapses in the ENS and respond to inflammatory stimuli (327). Cholinergic transmission between VN and reticuloendothelial organs is extensively required in maintaining arterial blood pressure, heart rate variability and modulate the innate and adaptive immune response (328). An increased proinflammatory cytokine storm is known to correspond to reduced VN activity in several inflammatory diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), sepsis, IBD (329–332). Activating the vagal efferent releases ACh at the distal end of the VN and effector ENS, inhibiting the release of proinflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-18), forming the CAP (295, 333, 334). The CAP is a highly conserved pathway and plays an important role in controlling morbidity and mortality associated with various human diseases, such as endotoxemia, sepsis, IBD, and RA (293). VNS implants in patients with resistant epilepsy showed LPS-induced release of TNF-α, IL-1β, and IL-6 in post-VNS blood. Also, in the RA cohort, patients showed reduced disease severity with reduced TNF-α levels in peripheral blood samples (335, 336).

This pathway can aggressively target innate immune cells and proinflammatory cytokine production. Therefore, it is proposed as a potential therapeutic target for mitigating several infections, including sepsis and the cytokine storm recently reported in SARS-CoV-2 infection (337, 338). The neuronal circuits that control TNF-β production in macrophages and other innate cells in the spleen lack the enzymatic machinery for ACh production. Rosas-Ballina et al. identified an important connection of the inflammatory reflex by discovering the cholinergic machinery in the memory CD4⁺ T cells in the spleen (259, 339). Further, this lymphocyte-produced ACh regulates the innate immune response in the local tissue microenvironment (340). Given the importance of cholinergic signaling in inflammatory reflexes, several drugs and molecules originally designed for neurological diseases draw attention as potential drugs for inflammatory diseases. Some of the drugs that interfere with neuroimmune communication and affect inflammation and immunity are listed in Tables 3 and 4. Further, we discussed the notable cholinergic agents used in humans.

Cholinergic Agonists

Nicotine acts as a pan-agonist of various homomeric nAChRs including α7-nAChR, β2-nAChR, α3-nAChR, α4-nAChR, and α5-nAChR. However, in epidemiological and clinical trials, nicotine-induced addiction and toxicity leading to several autonomic dysfunctions, cardiovascular malfunctions, tumorigenesis, and neuropathic pain (341–344). Various selective cholinergic agonists are exploited in clinical research to reduce the adverse effects of non-selective receptor activation and cytokine dysregulation in various inflammatory conditions. Some of these selective agonists are discussed below-

GTS-21 [3-(2,4-dimethoxy-benzylidene) anabaseine]

GTS-21 (also known as DMBX-A) is an orally active small molecule and a selective α7-nAChR agonist used in clinical trials for AD and schizophrenia, shown to enhance memory and cognitive activity (345). GTS-21 is also known to attenuate the production of proinflammatory cytokines TNF-α and IL-1β from monocytes stimulated with Toll-like receptor (TLR) agonists (346). GTS-21 inhibits Akt and NF-κB signaling pathway, thereby reducing the LPS-induced cytokine production in macrophages (347). It has recently been shown that GTS-21 ameliorates polymicrobial sepsis-induced hepatic injury by modulating autophagy (348). GTS-21 is known to inhibit the differentiation of DCs and controls collagen-induced arthritis in mice (287). In human endotoxemia, GTS-21 induces an anti-inflammatory function (349), and higher GTS-21 concentration in the plasma significantly correlated with the lower amount of TNF-α, IL-6, and IL-1RA but not IL-10 (349, 350). It has been reported that chronic obstructive pulmonary disease (COPD) patients have high levels of IL-6 and nitric oxide (NO), and GTS-21 treatment suppresses the IL-6 and NO levels in plasma by modulating the function of PBMCs (351). In RA patients, GTS-21 suppresses the differentiation of Th1 cells and IFN-γ production in PBMCs (352). This drug has also displayed promising results in clinical trials for AD, schizophrenia, ameliorating disease severity in sepsis, pancreatitis, and inflammation induced by traumatic brain injury (353–355).

ABT-126

The α7-nAChR is an extensively studied cholinergic receptor for developing new drugs that will ameliorate cognitive deficiencies, neuropsychiatric disorders, inflammation, and autoimmune diseases. ABT-126 (trade name Neonicline) is a small molecule allosteric modulator of α7-nAChR. ABT-126 is a safe and well-tolerated α7-nAChR agonist. A phase II randomized controlled multi-center clinical trial showed a pro-cognitive effect in mild to moderate dementia AD patients (356). Phase II trials with ABT-126 also improved schizophrenia-associated cognitive impairment in non-smokers compared to smokers (357). A detailed study on the effect of ABT-21 on different immune parameters is yet to be studied. Given its importance, ABT-126 will be of great value in exploring an effective target for treating critical inflammatory and autoimmune diseases.

CNI-1493

CNI-1493 (also known as Semapimod) is an anti-amyloidogenic and vagal output stimulant that inhibits systemic inflammation via CAP (358). CNI-1493 was synthesized as an endogenous inhibitor of the synthesis of nitric oxide (NO) and inflammatory cytokines in the CNS (359, 360). In the pre-clinical AD model, CNI-1493 has a neuroprotective effect by inhibiting amyloid oligomers’ formation and subsequently suppressing the production of IL-6 and TNF-α (361). CNI-1493 has been shown to inhibit LPS-induced TNF-α, IL-1α, IL-1, IL-6, and IL-8 in macrophages and monocytes but not in T cells (362, 363). In acute bacterial infection, CNI-1493 has been reported to reduce the inflammatory response by inhibiting NO synthesis in macrophages and promoting ROS production in granulocytes (364). In the EAE model, CNI-1493 treatment has been shown to reduce DC maturation and T cell priming (365). CNI-1493 was also found to have a protective effect in clinical trials in gut inflammatory diseases like Crohn’s disease and pancreatitis (366, 367).

Pilocarpine

Pilocarpine is a natural alkaloid extracted from the plant Pilocarpus. It acts as a muscarinic agonist and is used to treat the autoimmune Sjogren’s syndrome. It stimulates saliva secretion, aqueous tears from lacrimal glands, and mucin from goblet cells (368, 369). Pilocarpine hydrochloride has been shown to inhibit Candida albicans biofilm formation and its pathogenicity (370). In the rat model of epilepticus seizure, intraperitoneal pilocarpine injection promotes activation of cholinergic neurons and dysregulation of brain homeostasis (371–373). It is known to have no severe side effects in humans as a parasympathomimetic drug (374). Its role in modulating immunological components in infection, cancer, and autoimmunity needs further investigation.

Acetylcholinesterase (AChE) inhibitors

Inhibitors of acetylcholinesterase (EC 3.1.1.7), such as galantamine, donepezil, huperzine, and rivastigmine, are some of the drugs approved for human use to treat AD, MS, and dementia (375). Most AChEIs are competitive inhibitors of AChE and allosteric modulators of nAChRs. During inflammation, the increased levels of ACh in the plasma cause these molecules to form a complex with exovesicular AChE, leading to increased nitric oxide efflux from endothelial cells (376). The AChE molecules can terminate activation of the cholinergic anti-inflammatory pathway on red blood cells (RBCs) surface (377). The AChE bound on RBCs’ surface can inactivate the plasma ACh and may enhance inflammation (376, 378). AChEI linked to the RBC membrane through a glycosylphosphatidylinositol (GPI) anchor also serves as an age marker for RBCs (377). AChEI modulates the anti-inflammatory pathway and helps in the release of ACh to compensate for the reduced number of AChRs in inflammatory and neurodegenerative diseases. Several AChEIs cross the blood-brain barrier and inhibit AChE and BChE in both the central and peripheral nervous systems. These are listed in Table 3. AChEIs are known to lower proinflammatory cytokines such as IFN-γ, IL-17, MCP-1, RANTES, TWEAK, and increase anti-inflammatory cytokines IL-4 and IL-10 (379).

Cholinergic Antagonists

Overexpression and altered parasympathetic inputs are often associated with the progression of ovarian, lung, skin cancers, and solid tumors (380, 381). Increased ACh signaling via M₁ mAChR, M₂ mAChR, and M₃ mAChR also contributes to asthma and COPD (382). Abnormal cholinergic activity leads to immune-related pathological conditions in several skin diseases like atopic dermatitis, psoriasis, pemphigus, and palmoplantar pustulosis (19, 383, 384). Aberrant expression of ACh components, namely CHT1, ChAT, VAChT, nAChR, mAChR, and OCT1, and its release in GI tracts contribute to pathological conditions like IBD, colon cancer, and pancreatitis (70, 385, 386). Below, we discussed some of the promising antagonistic agents currently used in humans.

Mecamylamine

Mecamylamine (also known as inversine) is an orally available, non-selective, and non-competitive antagonist of heteromeric α4β2 and α3β4 subtype of nAChRs, and it can cross the blood-brain barrier even at a low dose (387). It is extensively used as an anti-hypertensive, anti-addictive, and anti-depressant drug (387). Mecamylamine is known to abolish the impairment of macrophages and decrease the Mycobacterium tuberculosis burden induced by nicotine (388). In the presence of IL‐18, mecamylamine abolishes the nicotine-induced inhibition of adhesion molecules on monocytes and cytokine production by PBMC (143). The potential for its effectiveness in treating neuroimmune diseases requires further investigation.

Atropine

It is widely used in treating bradycardiaand inhibiting respiratory and oral secretion (389). In vitro treatment with atropine has been shown to reduce the production of IL-2 by concanavalin-A stimulated T cells and reduced the cytotoxicity of NK cells (390). Along with the suppression of T cell response, it significantly reduces tissue injury, leucocyte accumulation, and inflammatory reactions at the site of turpentine-induced inflammation (180). Atropine administration before LPS challenge in mice has been reported to reduce TNF-alpha and elevated IL-10 levels in the plasma, thus, having a protective role in endotoxic shock (233). Atropine is also shown to lower the IgA production in the small intestine of BALB/c mice (391). Currently, atropine is successfully used to treat myopia, IBD, and MG patients (392–394). However, its role in several neuroimmune and autoimmune diseases needs to be investigated.

Dicyclomine

Dicyclomine (also known as dicycloverine) is a selective M₁ mAChR antagonist having an antispasmodic effect and is effectively used for treating several GI conditions such as irritable bowel syndrome (IBS) and intestinal cramping (395, 396). However, its exact mode of action in controlling mucosal homeostasis remains elusive. Apart from its antimuscarinic activities, it also has anti-fungal properties against the human pathogen Candida albicans. It prevents the growth, adhesion, biofilm formation, and yeast to hyphal transformation in C. albicans by targeting gene transduction in both the cAMP pathway and MAPK cascade (397). Dicyclomine hydrochloride is also found to have antibacterial potential in animals challenged with Salmonella typhimurium via competitive inhibition of lipase activity (398, 399). The anti-cholinergic implication of dicyclomine on immunological components requires further study.

Tiotropium

Tiotropium (trade names, Spiriva, Braltus) is a long-acting M₃ mAChR antagonist that has an immunosuppressive function in allergic asthma and chronic obstructive pulmonary disease (COPD) and which improves airway remodeling (400). Tiotropium also reduces the Th2 cytokine production in mice (401), and antagonizes the LTB4 production in human alveolar macrophages (402). In vitro studies have demonstrated that the M₃ mAChR expressed on macrophages is responsible for producing pro-inflammatory cytokines like IL-8 and leukotriene B4 (LTB-4). LTB-4 is an inflammatory mediator that causes leukocyte adhesion, activation, and inflammatory cell recruitments. M₃ mAChR drives neutrophil recruitment via macrophage-derived chemotactic mediators (402). Tiotropium, an M₃ mAChR antagonist, shows anti-chemotactic properties and reduces the ROS-mediated cytotoxicity in alveolar macrophages, thus reducing cellular inflammation (403, 404).

Summary and Future Perspective

There is growing evidence suggesting bidirectional interactions between the nervous system and the immune system at the cellular and molecular levels. Understanding the multicellular and multidimensional signals involved and the regulatory mechanisms of immunological reflex in chronic and acute inflammatory diseases offer ample opportunity for basic and clinical research. Many neurodegenerative diseases have a close relationship with the activation of inflammation in the central nervous system and the peripheral immune system (405, 406). Given the importance of functional circuitry in the secondary lymphoid tissues (407), the cholinergic system’s influence on the immune system cannot be ignored while designing therapeutic strategies to treat even neurological disorders. In clinical trials (clinical trial registry numbers NCT00783068, NCT04470479, NCT00000172, NCT00892450), some cholinergic stimulators and pharmaceutical antagonists were used in various inflammatory diseases. These molecules can also alter the innate and adaptive response and need to be investigated further.

Further, the various activation mechanisms of the cholinergic system in different subsets of innate and adaptive immune cells need to be elucidated. A multidimensional and multifactorial systems biology approach could help connect various individual components, such as genetic disposition, cholinergic deficits, inflammatory mechanism, oxidative stress, mitochondrial dysfunction, and other neurotransmitter defects. Such an approach would serve well to understand neuro-immune diseases and may also help in customizing therapeutic regimens. The high degree of homology (64 to 68% sequence identity and 82 to 92% sequence similarity) between the transmembrane domains of mAChRs (250), makes designing small-molecule ligands that could selectively target specific mAChRs incredibly challenging. Recently, Biased M₁ mAChR-mutant mice were used to develop next-generation drugs for AD, which hold promise for the future (408).

Funding

NH received the Senior Research Fellowship from the Council of Scientific and Industrial Research. GL received grants from the Department of Biotechnology (Grants numbers, BT/PR15533/MED/30/1616/2015 and BT/PR14156/BRB/10/1515/2016) and Swarna Jayanti Fellowship (DST/SJF/LSA-01/2017-18) from Department of Science and Technology, Ministry of Science and Technology, Government of India.

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