Abstract
Multiple sclerosis (MS) is a common neurological disorder of putative autoimmune origin. Clinical and experimental studies delineate abnormal expression of specific cytokines over the course of the disease. One major cytokine that has been shown to play a pivotal role in MS is tumor necrosis factor (TNF). TNF is a pleiotropic cytokine regulating many physiological and pathological functions of both the immune system and the central nervous system (CNS). Convincing evidence from studies in human and experimental MS have demonstrated the involvement of TNF in various pathological hallmarks of MS, including immune dysregulation, demyelination, synaptopathy and neuroinflammation. However, due to the complexity of TNF signaling, which includes two-ligands (soluble and transmembrane TNF) and two receptors, namely TNF receptor type-1 (TNFR1) and type-2 (TNFR2), and due to its cell- and context-differential expression, targeting the TNF system in MS is an ongoing challenge. This review summarizes the evidence on the pathophysiological role of TNF in MS and in different MS animal models, with a special focus on pharmacological treatment aimed at controlling the dysregulated TNF signaling in this neurological disorder.
Highlights
Multiple sclerosis (MS) is a chronic neurodegenerative disease of the central nervous system (CNS)associated with uncontrolled inflammation and autoimmunity, as a result of an attack against central myelin by blood-borne autoreactive T lymphocytes [1]
Due to the complexity of the immune responses mediated by tumor necrosis factor (TNF) and for the aim of this review, we provide a brief overview on TNF role in T cell-subset function and we refer the reader to more detailed reviews on this topic [37,38]
In TNFR2 KO mice, the number and function of T regulatory cells (Tregs) were comparable with wild-type mice, Tregs failed to expand when stimulated under inflammatory conditions either in vivo or in vitro [55,60]
Summary
Multiple sclerosis (MS) is a chronic neurodegenerative disease of the central nervous system (CNS). Despite the clinically different phenotypes, which likely underlie distinct pathological processes [3,4], MS brains share some neuropathological hallmarks, which include multiple inflammatory demyelinated plaques distributed throughout the neuroaxis and characterized by infiltrating T cells, activated microglia and astroglia, synaptic loss and neurodegeneration [5,6]. CNS inflammation is proposed to drive neuronal damage in MS, by altering synaptic transmission from the very early stages of the disease [8]. We review the pleiotropic functions of TNF in both the immune system and the CNS, with a focus on those processes that are dysregulated in MS, such as Treg function, neuronal transmission, BBB permeability and myelination. We provide an updated overview of data from different animal models of MS and from MS patients about the role of TNF and its receptors in MS pathology, proposing a re-examination of therapies targeting TNF signaling in MS
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