Hypoxia in multiple sclerosis

Abstract

Low oxygen availability (hypoxia) is a prominent but poorly understood feature in multiple sclerosis (MS). Whether hypoxia causes or drives MS pathology and symptoms or whether it is a consequence of other pathological events, such as inflammation and vascular dysfunction, is unknown. Here, we summarize the available literature on the interplay between hypoxia and both pathological and symptomatic features of MS. Severe environmental hypoxia (i.e., altitude) may trigger or facilitate MS-related events, possibly by exacerbating tissue hypoxia in the central nervous system. Accordingly, increasing oxygen supply can mitigate pathological and clinical parameters in MS models. In contrast, stimulating the endogenous hypoxia response and adaptation systems by controlled exposure to hypoxia (hypoxia conditioning) renders the central nervous system more resistant to hypoxic insults, thereby attenuating pathology and symptomatology in MS models. Overlapping mechanisms likely play a role in the benefits conferred by physical activity in MS. We provide an integrative model to explain the paradoxically beneficial outcomes of both increased and decreased ambient oxygen conditions. In conclusion, controlled exposure to hypoxia, perhaps in combination with exercise, is a promising, possibly disease-course modifying therapeutic approach for MS. However, many open questions remain.

Keywords: Hypoxia inducible factor; Mitochondria; Neurodegeneration; Neuroinflammation; Oxidative stress; Oxygen sensing.

Fig. 1

Disease courses of multiple sclerosis (MS) and genetic and environmental factors. There are environmental and genetic risk factors associated with MS and its progression. Among the environmental risk factors, hypoxia is not well understood. Several genetic risk factors are related to hypoxia responses, including the gene encoding vascular endothelial growth factor (VEGF) and interleukin 7 receptor A (IL-7RA). Radiologically isolated syndrome (RIS) – as assessed by magnetic resonance imaging (MRI) – and clinically isolated syndrome (CIS) are preclinical manifestations that may be followed by relapses and clinical forms of MS: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS).

Fig. 2

Regulation of hypoxia inducible factors (HIFs). Various transcription factors and posttranslational processes regulate HIF stability and activity. Among them is the oxygen-dependent regulation via HIF prolyl hydroxylases (PHDs), which hydroxylate (OH) HIF α subunits, allowing recognition by the von Hippel Lindau (VHL) tumor suppression protein, polyubiquitination (Ub) and proteasomal degradation under normoxic conditions. In hypoxia, HIF α subunits stabilize, dimerize with β-subunits and regulate transcription of hundreds of genes via binding hypoxia response elements (HRE) and recruiting co-activators such as CREB binding protein (CBP) or p300.

Fig. 3

Hypoxia in multiple sclerosis (MS). Both “real” and “virtual” hypoxia characterize MS pathology and are results of reduced oxygen supply (e.g., hypoperfusion) or increased oxygen demand/mitochondrial damage, respectively (a). Hypoxia is involved in reduced blood-brain-barrier integrity, neuroinflammation and the formation of lesions and demyelination. At the level of the central nervous system (CNS, b) cerebral blood flow and oxygenation of brain and spinal cord are frequently impaired in MS and MS models. The anatomical peculiarities of some CNS areas make them especially vulnerable to hypoxia, and MS lesions preferentially are found in such locations. In addition, some brain regions are thought to link hypoxia and immunological pathologies in MS, among them the choroid plexus. See text for further descriptions.

Fig. 4

A model of differential effects of hyperoxia and hypoxia-interventions on multiple sclerosis features. Oxygen supplementation, intermittent and chronic hypoxia probably improve pathological tissue hypoxia and associated metabolic consequences by different ways (a). While hyperoxia and chronic continuous hypoxia probably are effective mainly during the intervention (blue bars), intermittent hypoxia approaches are thought to induce protective adaptations to hypoxia that may persist for some time after cessation of the intervention. A theoretical model about how the modulation of hypoxia inducible factor (HIF) pathways may be beneficial in both directions (up- and downregulation of HIF activity) is shown in panels b–j. Indicated are hypoxia responses (including HIF-activities) over time. The hypothetical lower (black) dashed line indicates the threshold that has to be reached for hypoxia responses to induce robust hypoxia adaptations (black bent arrows), while the upper (red) dashed line indicates a threshold for pathological/damaging hypoxia responses. A normal hypoxia response is characterized by low baseline levels and a robust response to a hypoxic stimulus (b). High baseline levels (c) of hypoxia-responses (including HIF abundance) are characteristic for tissue hypoxia (e.g., tumor hypoxia) and have been reported for some aging tissues – this may be also the case in some parts of the CNS, e.g., during periods with high inflammation or due to mitochondrial dysfunction, in MS. Low baseline levels of hypoxia responses and insufficient responses following a hypoxic stimulus to induce adaptations (d) may be the result of artificial oxygenation, e.g., hyperoxic treatments, or impaired/downregulated HIF-pathways (h). Upregulation of the hypoxia response can be detrimental, if the hypoxia response is already efficient (e) or if baselines are high already (f). It can be beneficial, if the hypoxia response is weak (g). HIF inhibition can be beneficial, if the baseline hypoxia response is high (i) and can further deteriorate an already weak hypoxia response (j).