The Peripheral Network between Oxidative Stress and Inflammation in Multiple Sclerosis

Abstract

Reactive oxygen species (ROS) are mainly produced by microglia and macrophages during inflammation-driven oxidative burst. However, they can in turn affect the reactivity and function of immune 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 of MBP (Myelin Basic Protein)-stimulated Peripheral Blood Mononuclear Cells (PBMCs) by flow-cytometry. In addition, blood Coenzyme-Q10 (CoQ10), 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 (CD14+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 CoQ10 (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 CD14+ IL10+ 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+ IL10+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 of this 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.