Chronic Mild Hypoxia Delays Th17 Response and Induces CXCL12 and CXCL13 in EAE

Background: In experimental autoimmune encephalomyelitis (EAE), and animal model of multiple sclerosis (MS), it is well documented that chronic inflammatory activity can lead to compromised delivery of oxygen and glucose at lesion sites. Therapeutic approaches geared to restoring metabolic balance may be useful.

Objectives: Previously, we have reported that in vivo exposure to chronic mild hypoxia (10% oxygen) leads to vascular remodeling that results in amelioration of myelin oligodendrocyte glycoprotein peptide (35-55) (MOG)-mediated EAE. In the present study we further define mechanisms. 

Methods: C57BL/6 mice were immunized with MOG and some of them were kept in the hypoxia chambers (day 0) and exposed to 10 % oxygen for 3 weeks, while the others were kept at normoxic environment. Sham immunized controls were included in both hypoxic and normoxic groups. Animals were sacrificed at pre-clinical and peak disease periods for tissue collection.

Results: Delayed disease onset, which was significant following exposure to 10% oxygen correlated with decreased evidence of inflammation in the spinal cord of immunized animals.  Decreased evidence of infiltration correlated with decreased numbers of CD4+ T cells in the hypoxic spinal cords and delayed Th17 specific cytokine responses. These observations did not appear to be due to hypoxia-induced changes in the ability of MOG peptide to induce a proliferative response of T-cells in this model. In addition, for the first time, here we presented evidence that exposure to chronic mild hypoxia induced a significant increase in the number of CD11b⁺CD45^lowmicroglia in the hypoxic EAE spinal cords. Chemokines CXCL12 and CXCL13 were significantly induced in the spinal cords of hypoxic EAE mice.

Conclusions: Results suggest that acclimatization to mild hypoxia incites a number of endogenous adaptations that modulate the inflammatory response so that this system can be used to pinpoint possible new therapeutic targets in neurodegenerative diseases.