title: Endogenous adaptation to low oxygen modulates T-cell regulatory pathways in EAE.
abstract: BACKGROUND
  In 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.
  
  
  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 and analysis.
  
  
  RESULTS
  Exposure 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.
  
  
  CONCLUSIONS
  Acclimatization 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.
authors.affiliation: Department of Neurology, School of Medicine, Wayne State University, Detroit, MI, 48201, USA. nesenbil@med.wayne.edu.
authors.forename: Nilufer
authors.initials: N
authors.lastname: Esen
authors.affiliation: Department of Neurology, School of Medicine, Wayne State University, Detroit, MI, 48201, USA. vkatyshev@med.wayne.edu.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Katyshev
authors.affiliation: Department of Neurology, School of Medicine, Wayne State University, Detroit, MI, 48201, USA. zserki@med.wayne.edu.
authors.forename: Zakhar
authors.initials: Z
authors.lastname: Serkin
authors.affiliation: Department of Neurology, School of Medicine, Wayne State University, Detroit, MI, 48201, USA. skatyshe@med.wayne.edu.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Katysheva
authors.affiliation: Department of Neurology, School of Medicine, Wayne State University, Detroit, MI, 48201, USA. pdduffy@med.wayne.edu.
authors.forename: Paula
authors.initials: P
authors.lastname: Dore-Duffy
mesh_terms: D000220:Adaptation, Biological / Q000502:physiology*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000473:pathology*; D005260:Female; D005620:Freund's Adjuvant / Q000276:immunology; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D020556:Neutrophil Infiltration; D010100:Oxygen / Q000008:administration & dosage*; D010446:Peptide Fragments / Q000633:toxicity; D013116:Spinal Cord / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D013997:Time Factors
chemical_list: D015703:Antigens, CD; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020381:Interleukin-17; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D007371:Interferon-gamma; D005620:Freund's Adjuvant; D010100:Oxygen