Oxidative stress in multiple sclerosis: Central and peripheral mode of action

Abstract

Accumulating evidence suggests that oxidative stress plays a major role in the pathogenesis of multiple sclerosis (MS). Reactive oxygen species (ROS), which if produced in excess lead to oxidative stress, have been implicated as mediators of demyelination and axonal damage in both MS and its animal models. One of the most studied cell populations in the context of ROS-mediated tissue damage in MS are macrophages and their CNS companion, microglia cells. However, and this aspect is less well appreciated, the extracellular and intracellular redox milieu is integral to many processes underlying T cell activation, proliferation and apoptosis. In this review article we discuss how oxidative stress affects central as well as peripheral aspects of MS and how manipulation of ROS pathways can potentially affect the course of the disease. It is our strong belief that the well-directed shaping of ROS pathways has the potential to ameliorate disease progression in MS.

Keywords: DMF; Neurodegeneration; Neuroprotection; Nrf2.

Fig. 1

Scheme of Nrf2 activation. Under basal conditions, Nrf2 interacts with Keap1, which results in degradation of Nrf2. In response to cellular stress, Nrf2 is liberated from its cytosolic inhibitor, trans-locates into the nucleus and binds to antioxidant response elements (AREs) in the promoters of target genes. Nrf2-regulated genes mainly include genes coding for antioxidative and detoxifying enzymes.

Fig. 2

T_reg cells fail to control effector T cells in the periphery and in the CNS under auto-immune conditions. In peripheral lymph nodes, DCs activate T cells and induce their differentiation towards inflammatory T_h1 and T_h17 cells by the release of cytokines, like IL-6 and IL23 (T_h17) and IL-12 (T_h1). In MS, T_reg cells eventually fail to control this T cell activation process. Activated T cells migrate to and enter the CNS where they become reactivated by local APCs, and again are not adequately suppressed by T_reg cells. T_eff cells then expand and drive CNS inflammation. After having successfully entered the CNS, T cells are exposed to a completely novel oxidative milieu. There, ROS molecules are mainly produced by macrophages, microglia and astrocytes and lead to damage of neurons, axons, myelin and oligodendrocytes (indicated by arrows). MDSCs can suppress activated T cells, but can also differentiate into dendritic cells and macrophages in the CNS and influence the entire scenario.

Fig. 3

Redox regulation of T cell activation. (A) Induction of T_reg cells by macrophages is dependent on ROS production (Kraaij et al., 2010). (B) Sustained pro-oxidant extracellular conditions inhibit T cell activation and induce apoptosis in T cells (Tripathi and Hildeman, 2004). (C) Interaction of DCs with T cells leads to cysteine accumulation in the extracellular space, which produces an extracellular redox potential promoting T cell proliferation (Angelini et al., 2002). (D) T_reg cells inhibit dendritic cell induced extracellular reduced redox potential (Yan et al., 2010).

Fig. 4

Immunomodulatory and neuroprotective effects of FAEs. FAEs activate the cellular stress response by activating Nrf2 and thereby protect neurons and oligodendroytes from oxidative injury (Linker et al., 2011). In addition, FAEs reduce secretion of proinflammatory cytokines by astrocytes and macrophages (Lin et al., 2011, Wilms et al., 2010). FAEs inhibit leukocyte migration and thereby infiltration of immune cells in the CNS (Dehmel et al., 2014, Rubant et al., 2008). In the periphery FAEs reduce DC maturation and release of DC cytokines driving a T_h1/T_h17 response (de Jong et al., 1996). FAEs might also directly mediate a shift towards T_h2 instead of T_h1 differentiation (Litjens et al., 2004). How FAEs affect MDSC function and/or differentiation towards inflammatory APCs remains to be elucidated.