Abstract
Multiple sclerosis (MS) is characterized by pro-inflammatory cytokine production. Acetylcholine (ACh) contributes to the modulation of central and peripheral inflammation. We studied the homeostasis of the cholinergic system in relation to cytokine levels in immune cells and sera of relapsing remitting-MS (RR-MS) patients. We demonstrated that lower ACh levels in serum of RR-MS patients were inversely correlated with the increased activity of the hydrolyzing enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Interestingly, the expression of the ACh biosynthetic enzyme and the protein carriers involved in non-vesicular ACh release were found overexpressed in peripheral blood mononuclear cells of MS patients. The inflammatory state of the MS patients was confirmed by increased levels of TNFα, IL-12/IL-23p40, IL-18. The lower circulating ACh levels in sera of MS patients are dependent on the higher activity of cholinergic hydrolyzing enzymes. The smaller ratio of ACh to TNFα, IL-12/IL-23p40 and IL-18 in MS patients, with respect to healthy donors (HD), is indicative of an inflammatory environment probably related to the alteration of cholinergic system homeostasis.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by the presence of sclerotic plaques that impair correct neuronal signal transmission [1]
In order to evaluate whether the lower levels of ACh were dependent on a defect in ACh synthesis and/or hydrolysis, first of all, in the same RR-MS patients and healthy donors (HD) subjects we evaluated the activity of the ACh hydrolyzing enzymes AChE and BuChE
First of all, we have confirmed in a larger number of patients that ACh levels were significantly reduced in sera of RR-MS subjects, and, in order to better understand the involvement of ACh in the pathogenesis of MS, we have investigated the possible causes responsible for decreased ACh levels
Summary
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by the presence of sclerotic plaques that impair correct neuronal signal transmission [1]. The aetiology is still unclear, it is widely accepted that MS is caused by T cell auto-reactivity. These cells recognize some myelin like-proteins as “non-self”, causing the spread of an inflammatory response in the brain and spinal cord, leading to the destruction of myelin sheets. The major regulators of the immune system, play a key role in modulating the inflammatory cascade in MS. IL-12 and IL-23 promote the development of Th1-type immune responses affecting the synthesis of several other cytokines including TNFα and IFNγ. Increased expression of IL-12p40 detected in acute MS plaques confirmed the pathogenic role for IL-12 in MS [2]. Together with IL-12, IL-18 acts as a link between innate and adaptive immune responses and participates in the pathogenesis of MS [3]
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