Possible Correlation between Cholinergic System Alterations and Neuro/Inflammation in Multiple Sclerosis.

Valentina Gatta,Guadalupe Mengod,Ada Maria Tata,Marcella Reale

doi:10.3390/biomedicines8060153

Abstract

Multiple sclerosis (MS) is an autoimmune and demyelinating disease of the central nervous system. Although the etiology of MS is still unknown, both genetic and environmental factors contribute to the pathogenesis of the disease. Acetylcholine participates in the modulation of central and peripheral inflammation. The cells of the immune system, as well as microglia, astrocytes and oligodendrocytes express cholinergic markers and receptors of muscarinic and nicotinic type. The role played by acetylcholine in MS has been recently investigated. In the present review, we summarize the evidence indicating the cholinergic dysfunction in serum and cerebrospinal fluid of relapsing–remitting (RR)-MS patients and in the brains of the MS animal model experimental autoimmune encephalomyelitis (EAE). The correlation between the increased activity of the cholinergic hydrolyzing enzymes acetylcholinesterase and butyrylcholinesterase, the reduced levels of acetylcholine and the increase of pro-inflammatory cytokines production were recently described in immune cells of MS patients. Moreover, the genetic polymorphisms for both hydrolyzing enzymes and the possible correlation with the altered levels of their enzymatic activity have been also reported. Finally, the changes in cholinergic markers expression in the central nervous system of EAE mice in peak and chronic phases suggest the involvement of the acetylcholine also in neuro-inflammatory processes.

Highlights

We summarize the data indicating the possible involvement of ACh in demyelinating disease such as multiple sclerosis (MS), reporting recent data demonstrating how the alteration of the cholinergic system activity is present in Multiple sclerosis (MS) patients and in experimental autoimmune encephalomyelitis (EAE) mice, may be correlated with the immune system dysfunction and alterations of the neuro-inflammatory processes characterizing the MS pathology
The higher gene expression level of several cytokines, such as IL-1β, IL-12/IL-23p40, IL-17, IL-18 and TNFα was detected in relapsing–remitting course of the disease (RR-MS) compared to healthy subjects (HS), according to with the levels measured in the serum; this confirms the relationship between expression and production of pro-inflammatory cytokines in MS patients [35]
Understanding the mechanisms leading to aberrant immune response and the severe neuro-inflammation in MS plays a relevant role in the development of new treatments directed to decrease pro-inflammatory cytokine production and to ameliorate the clinical symptoms, slowing the disease outcome and delaying or arresting the onset of the disabilities

Summary

Acetylcholine and Immune System

ACh can be produced by non-neuronal cells, such as keratinocytes and endothelial cells, contributing to local regulation of the cell physiology [4,5,6]. The immune cells express muscarinic receptors whose selective activation modulates the synthesis and production of pro-inflammatory cytokines contributing to modulating the inflammatory processes and, albeit they are not involved in the regulation of the antibodies’ synthesis, they favor the antibody class switching from IgM to IgG1 [18,19]. The immune cells express different nicotinic receptor subunits (α2, α4, α 5, α9, α7 and β1, β2) whose combination contributes to the hetero- or homopentameric receptor subtype formation. The homopentameric α7 nAChR is the best characterized nicotinic receptor subtype in the immune system This receptor appears mainly involved in the inhibition of inflammatory processes modulating the production of the anti-inflammatory cytokine, suppressing dendritic cells and macrophage activity and leading to the suppression of T cell differentiation [21,22]. We summarize the data indicating the possible involvement of ACh in demyelinating disease such as multiple sclerosis (MS), reporting recent data demonstrating how the alteration of the cholinergic system activity is present in MS patients and in experimental autoimmune encephalomyelitis (EAE) mice, may be correlated with the immune system dysfunction and alterations of the neuro-inflammatory processes characterizing the MS pathology

Cholinergic Dysfunction in Multiple Sclerosis

The Interface between Cholinergic System and Inflammatory Cytokines in MS

Genetic

Cholinergic Markers Alteration in the Brain of EAE Mice

Findings

Conclusions