New Insights in the Mechanisms of Impaired Redox Signaling and its Interplay With Inflammation and Immunity in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is an autoimmune neurological disease characterized by chronic inflammation of the central nervous system (CNS), leading to demyelination and axonal damage and resulting in a range of physical, mental or even psychiatric symptoms. Key role of oxidative stress (OS) in the pathogenesis of MS has been suggested, as indicated by the biochemical analysis of cerebrospinal fluid and blood samples, tissue homogenates, and animal models of multiple sclerosis. OS causes demyelination and neurodegeneration directly, by oxidation of lipids, proteins and DNA but also indirectly, by inducing a dysregulation of the immunity and favoring the state of pro-inflammatory response. In this review, we discuss the interrelated mechanisms of the impaired redox signaling, of which the most important are inflammation-induced production of free radicals by activated immune cells and growth factors, release of iron from myelin sheath during demyelination and mitochondrial dysfunction and consequent energy failure and impaired oxidative phosphorylation. Review also provides an overview of the interplay between inflammation, immunity and OS in MS. Finally, this review also points out new potential targets in MS regarding attenuation of OS and inflammatory response in MS.

Detection of galanin receptors in the spinal cord in experimental autoimmune encephalomyelitis

“…Multiple sclerosis (MS) is an autoimmune neurological disease characterized by chronic inflammation of the central nervous system (CNS), resulting in a range of physical, mental and psychiatric symptoms 1,2 . The pathophysiology of MS is not fully elucidated.…”

Thinking outside the box: non-canonical targets in multiple sclerosis

“…Neuronal — as well as oligodendroglial — death in MS is also associated with oxidative stress 220 . Reactive oxygen species are critically involved in neurodegeneration 221 , particularly during an acute immune attack targeting the myelin sheath 222 , and the co-factors NADPH and NADH are pivotal for neuronal redox homeostasis.…”

Melatonin and multiple sclerosis: antioxidant, anti-inflammatory and immunomodulator mechanism of action

“…There are four types of MS: progressive relapsing, primary-progressive, relapsing–remitting (RRMS), and secondary-progressive (SPMS) (Compston and Coles 2002 , 2008 ; Bahamonde et al 2014 ), with RRMS, being the main form of the disease (Adamczyk-Sowa et al 2016b ) affecting 85% of patients (Michaličková et al 2020b ). In the four types of MS there is neurodegeneration and inflammation, but the RRMS is characterized by the appearance of symptoms, followed by a period of clinical remission (Adamczyk-Sowa et al 2016b ).…”

“…In addition, in the study made by Conde et al, 2019 , for the first time, the presence of intense oxidative stress in non-nervous organs in the animal MS model, experimental autoimmune encephalomyelitis (EAE), was verified, which suggests that something similar may occur in MS patients (Conde et al 2019 ). During the course of the disease, the infiltration of autoreactive effector T cells Th1 and Th17 into the CNS, causes an increase in pro-inflammatory cytokines (Interferon-γ (IFN-γ), the tumoral necrosis factor (TNF), Interleukin-17 (IL-17) (van den Hoogen et al 2017 ) and Interleukin-22 (IL-22)), which attack the myelin sheath (Michaličková et al 2020b ). After the inflammatory reaction, the permeability of the BBB is increased by the action of the matrix metalloproteinase-9 (MMP-9), and other immune cells such as B lymphocytes and monocytes are recruited (Adamczyk-Sowa et al 2016a ; Michaličková et al 2020a ) (Fig.…”

“…It was observed that inflammasome NLRP3, plays a vital role in MS (Feng et al 2021 ). The activation of NF-κB, together with that of pro-caspase 1 are the two signals required to activate this inflammasome (Michaličková et al 2020b ). When NLRP3 is active, it causes a proteolytic activation of caspase-1, enabling the secretion of the pro-inflammatory cytokines IL-1β and IL-18 (Lahooti et al 2021 ) and also regulates the response of cells Th1 and Th17 (Feng et al 2021 ) (Fig.…”