The Peripheral Network between Oxidative Stress and Inflammation in Multiple Sclerosis

Abstract

M.R. and R.E contributed equally to this workReactive oxygen species(ROS) are mainly produced by microglia and macrophages during inflammationdriven oxidative burst. However, they can in turn affect the reactivity and function ofimmune cells.For the first time, the relationship between these two key players involved in Multiple Sclerosis (MS) was evaluated at peripheral level. We performed an in-depth immune-phenotypic and functional analysis ofMBP (Myelin Basic Protein)-stimulated Peripheral Blood Mononuclear Cells (PBMCs) by flow-cytometry. In addition, blood Coenzyme-QI0 (CoQI0), total, oxidized and reduced forms of glutathione (GSTot, GSSG, GSH), malondialdehyde (MDA), ROS, anti-oxidized-low-density-lipoproteins antibodies (anti-oxLDL), and anti-oxidant-power (PAO) were studied in 31 untreated MS patients (MSnoTP), 23 MS patients (MSTP) treated with Disease Modifying Drugs (DMDs) and 39 matched controls (HC). The focus of our study was the correlation between oxidative stress biomarkers and distribution of immune-phenotypes across the 3 studied groups. In MSnoTP an inverse correlation between MDA and apoptotic cells (CD4+ AnnexinV+ TIM3+) was detected (rs= -0.50, p= 0.01). Ml functional phenotype (CDI4+ IL6+) and TH17 cells (CD4+ IL22+) inversely (rs= -0.48) and directly (rs= 0.46) correlated (p = 0.01) with Anti-oxLDL antibodies and GSSG, respectively. The latter direct correlation was shown also in MSTP. Notably, in this group, we also detected a direct correlation between CD4+ IL4+ and CD4+ IL25+ (TH2 phenotype) with CoQI0 (rs= 0.54) and GSH (rs= 0.46) (p< 0.03), two crucial anti-oxidants. Again, a direct correlation was found between CD8+ BDNF+ cells (suppressor phenotype) and anti-oxLDL (rs= 0.48, p= 0.03). Surprisingly, we measured an inverse correlation between CDI4+ ILI0+ cells (M2 immune-regulatory cells) with GSH (rs= -0.59, p< 0.001). Our findings endorse the idea of a relationship between pro-inflammatory cells and pro-oxidative environment, even at peripheral level. Interestingly, the correlation between CD4+ ILIO+ cells and a defective anti-oxidant equipment might be regarded as evidence of the involvement of these cells during an inflammatory/oxidative phase that they try to control. The finding ofthis link only in MSTP patients might suggest that DMDs can provide an alternative way to counteract inflammation, regardless of an absolute increase of these immune-regulatory cells.

The Influence of Reactive Oxygen Species in the Immune System and Pathogenesis of Multiple Sclerosis

“…Numerous studies have shown that neuroinflammation and oxidative stress are concurrently involved in the pathogenesis of MS. Noticeably, oxidative stress plays a pivotal role in the initiation and progression of MS [ 90 , 117 ].…”

“…One of the factors that may regulate the pathogenesis of MS is endogenous antioxidant enzyme systems. Several reports have highlighted the increased expression of antioxidant enzymes, such as SOD1 and SOD2, and catalase in actively demyelinating MS lesions; hence, increased expression of antioxidant enzymes in inflammatory MS lesions is associated with neuroinflammation [ 117 , 128 ]. The inflammation and cell death in the brain could be regulated by Nrf2.…”

Impact of Mast Cells on Multiple Sclerosis: Inhibitory Effect of Natalizumab

“…Mast cells stimulate activated T cells, and this effect is further increased when MCs are activated by myelin and is in part dependent on TNF alpha. MS is a predominantly Th l-cell-mediated disease, therefore, it appears that inflammatory response in MS patients (27) involve cytokine release and MC mediators, including other inflammatory cells such as macrophages and lymphocytes. Although mast cell-mediated demyelination is largely assumed to be a T-cell-dependent process, driven by a myelinspecific auto-antigen (l).…”

The Plasticity of Immune Cell Response Complicates Dissecting the Underlying Pathology of Multiple Sclerosis

“…Human MCs release matrix metalloproteinase-9 and IL-6 in response to activated T cells, and myelin, which is partially regulated by TNF α , stimulates MCs in a way that increases the number of activated T cells. MS [ 278 ], a Th1-cell-mediated illness, displays an inflammatory response that includes the production of cytokines and MC mediators in addition to other inflammatory cells like lymphocytes and macrophages. Though it is widely acknowledged that MC-mediated demyelination, which is brought on by an auto-antigen specific to myelin, requires T-cells [ 279 ].…”