Chronic Mild Hypoxia Exposure Altered T Cell Subsets and Endothelial Activation Markers in EAE

Background: The mammalian brain depends on a continuous supply of oxygen and glucose to meet metabolic demand. There are mechanisms which allow the brain to exist under low oxygen conditions when ‘idling’ but increased oxygen delivery to the neurons and other cells of the central nervous system (CNS) when activated.  Regulation involves numerous intrinsic and extrinsic adaptive mechanisms that maintain metabolic homeostasis. Exposure to chronic mild hypoxia induces a number of adaptive changes in the brain that promote survival. 

Objectives: We have questioned whether endogenous adaptation to a stressor such as mild changes in respiratory oxygen alters chronic inflammation in an animal model of multiple sclerosis (MS) experimental autoimmune encephalomyelitis (EAE). We previously reported that when mice were exposed to chronic mild hypoxia at the time of immunization they exhibited a delay in disease onset and decreased severity of symptoms. Delayed onset of EAE was associated with decreased T cell infiltration into the spinal cord as well as altered regulatory T-cell subsets.  

Methods: In this study, we examine the effect of exposure to mild hypoxia during the chronic phase of EAE.  Mice were exposed to 10% oxygen after development of peak disease for 3 weeks. Then the inflammatory T cells infiltrate into the spinal cord were isolated and analyzed using flowcytometry. Endothelial activation markers V-CAM and I-CAM were also evaluated by immunofluorescence staining in the spinal cord tissue sections, and the isolated microvessels. 

Results: Chronic exposure to mild hypoxia ameliorated chronic inflammatory activity. Amelioration of chronic inflammation was associated with reduction in clinical score, and decreased evidence of spinal lesions. Exposure to hypoxia increased the ratio of Foxp3+ Tregs and IL-10+ T helper cells that have been shown to have anti-inflammatory function.  Exposure to hypoxia also increased vascular density and decreased evidence of endothelial activation that may affect blood brain barrier (BBB) permissiveness.

Conclusions: These results imply that endogenous adaptive mechanisms induced in response to mild hypoxic stress ameliorate EAE.  The mechanisms may be complex and may involve vascular remodeling, restoration of vascular quiescence, and promotion of regulatory immune cells.