Endogenous adaptation to low oxygen modulates T-cell regulatory pathways in EAE

Abstract

BackgroundIn the brain, chronic inflammatory activity may lead to compromised delivery of oxygen and glucose suggesting that therapeutic approaches aimed at restoring metabolic balance may be useful. In vivo exposure to chronic mild normobaric hypoxia (10 % oxygen) leads to a number of endogenous adaptations that includes vascular remodeling (angioplasticity). Angioplasticity promotes tissue survival. We have previously shown that induction of adaptive angioplasticity modulates the disease pattern in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). In the present study, we define mechanisms by which adaptation to low oxygen functionally ameliorates the signs and symptoms of EAE and for the first time show that tissue hypoxia may fundamentally alter neurodegenerative disease.MethodsC57BL/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 and analysis.ResultsExposure to mild hypoxia decreased histological evidence of inflammation. Decreased numbers of cluster of differentiation (CD)4+ T cells were found in the hypoxic spinal cords associated with a delayed Th17-specific cytokine response. Hypoxia-induced changes did not alter the sensitization of peripheral T cells to the MOG peptide. Exposure to mild hypoxia induced significant increases in anti-inflammatory IL-10 levels and an increase in the number of spinal cord CD25+FoxP3+ T-regulatory cells.ConclusionsAcclimatization to mild hypoxia incites a number of endogenous adaptations that induces an anti-inflammatory milieu. Further understanding of these mechanisms system may pinpoint possible new therapeutic targets to treat neurodegenerative disease.

Endogenous Adaptation to Chronic Mild Hypoxia Shifts the Balance towards Anti-Inflammatory Milieu in Progressive Myelin Oligodendrocyte Glycoprotein Induced EAE

“…Vascular density in the spinal cord was determined in immunized mice exposed to normoxic and hypoxic conditions. Changes in vascular density in EAE and in response to low oxygen have been reported in our previous publications [13,14].…”

“…We reported that acclimatization to chronic mild hypoxia ameliorates the signs and symptoms of encephalomyelitis [13]. Exposure of mice to 10% oxygen significantly delayed the onset of clinical disease as well as reduced disease severity [14]. Changes in clinical disease was associated with decreased evidence of pathological disease as well as changes in T-cell effector and suppressor function.…”

“…Changes in clinical disease was associated with decreased evidence of pathological disease as well as changes in T-cell effector and suppressor function. While the exact mechanisms are still unclear, they are likely to be highly complex and may involve changes in both vascular function as well as the immune system [13][14][15].…”

“…We first examined section of lumbar spinal cord for expression of the endothelial activation marker VCAM. Results in Figure 5a indicate that expression of VCAM was de-nal cords [14]. Do determine if that is the case when hypoxia exposure starts after the disease onset, we first determine the total number of infiltrating T cells.…”

“…It is well established that encephalitogenic T cells, especially the IL-17+ T cells play a major role in the pathogenesis of EAE [18]. While the presence of CD4+ cells in the spinal cord is highly correlated to disease severity [14,19], the presence of regulatory T cells [CD25+FoxP3+ regulatory T cells (Tregs)] can dampen neuro-inflammation. We examined the effect of chronic mild hypoxia on regulatory T cell subsets (FoxP3 expressing CD25+ T regs, Blimp1+, and IL-10+ CD4 T cells) along with encephalithogenic T cells (IFNγ+ cells, and IL-17+ cells).…”