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

Journal of Neuroinflammation

Paula Dore-Duffy¹  Svetlana Katysheva¹  Zakhar Serkin¹  Vladimir Katyshev¹  Nilufer Esen¹ 

[1]Department of Neurology, School of Medicine, Wayne State University, Detroit 48201, MI, USA

关键词: T-regulatory cells;    IL-17;    HIF-1α;    Microvessels;    Angioplasty;    Adaptation;    Hypoxia;    EAE;    Multiple sclerosis;   

Others  :  1235582
DOI  :  10.1186/s12974-015-0407-4

 received in 2015-06-29, accepted in 2015-09-30,  发布年份 2016

【 摘 要 】

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.

【 授权许可】

   
2016 Esen et al.

【 图 表 】

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【 参考文献 】

• [1]Becher B, Segal BM: T(H)17 cytokines in autoimmune neuro-inflammation. Curr Opin Immunol 2011, 23(6):707-12.
• [2]Compston A, Coles A: Multiple sclerosis. Lancet 2008, 372(9648):1502-17.
• [3]Nylander A, Hafler DA: Multiple sclerosis. J Clin Invest 2012, 122(4):1180-8.
• [4]Trapp BD, Nave KA: Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 2008, 31:247-69.
• [5]Balabanov R, Beaumont T, Dore-Duffy P: Role of central nervous system microvascular pericytes in activation of antigen-primed splenic T-lymphocytes. J Neurosci Res 1999, 55(5):578-87.
• [6]Dore-Duffy P, Washington R, Dragovic L: Expression of endothelial cell activation antigens in microvessels from patients with multiple sclerosis. Adv Exp Med Biol 1993, 331:243-8.
• [7]Fisher M: Injuries to the vascular endothelium: vascular wall and endothelial dysfunction. Rev Neurol Dis 2008, 5(Suppl 1):S4-11.
• [8]Tan KH, Purcell WM, Heales SJ, McLeod JD, Hurst RD: Activated T cells mediate direct blood–brain barrier endothelial cell death and dysfunction. Neuroreport 2002, 13(18):2587-91.
• [9]Grammas P, Martinez J, Miller B: Cerebral microvascular endothelium and the pathogenesis of neurodegenerative diseases. Expert Rev Mol Med 2011, 13:e19.
• [10]Harik N, Harik SI, Kuo NT, Sakai K, Przybylski RJ, LaManna JC: Time-course and reversibility of the hypoxia-induced alterations in cerebral vascularity and cerebral capillary glucose transporter density. Brain Res 1996, 737(1–2):335-8.
• [11]Krizanac-Bengez L, Mayberg MR, Janigro D: The cerebral vasculature as a therapeutic target for neurological disorders and the role of shear stress in vascular homeostatis and pathophysiology. Neurol Res 2004, 26(8):846-53.
• [12]Lassmann H: Hypoxia-like tissue injury as a component of multiple sclerosis lesions. J Neurol Sci 2003, 206(2):187-91.
• [13]Trapp BD, Stys PK: Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol 2009, 8(3):280-91.
• [14]Dore-Duffy P, LaManna JC: Physiologic angiodynamics in the brain. Antioxid Redox Signal 2007, 9(9):1363-71.
• [15]Hawkins BT, Davis TP: The blood–brain barrier/neurovascular unit in health and disease. Pharmacol Rev 2005, 57(2):173-85.
• [16]Ward NL, LaManna JC: The neurovascular unit and its growth factors: coordinated response in the vascular and nervous systems. Neurol Res 2004, 26(8):870-83.
• [17]Ding YH, Ding Y, Li J, Bessert DA, Rafols JA: Exercise pre-conditioning strengthens brain microvascular integrity in a rat stroke model. Neurol Res 2006, 28(2):184-9.
• [18]Padilla J, Simmons GH, Bender SB, Arce-Esquivel AA, Whyte JJ, Laughlin MH: Vascular effects of exercise: endothelial adaptations beyond active muscle beds. Physiology (Bethesda) 2011, 26(3):132-45.
• [19]Zheng Q, Zhu D, Bai Y, Wu Y, Jia J, Hu Y: Exercise improves recovery after ischemic brain injury by inducing the expression of angiopoietin-1 and Tie-2 in rats. Tohoku J Exp Med 2011, 224(3):221-8.
• [20]Berchtold NC, Castello N, Cotman CW: Exercise and time-dependent benefits to learning and memory. Neuroscience 2010, 167(3):588-97.
• [21]Koutsioumpa M, Drosou G, Mikelis C, Theochari K, Vourtsis D, Katsoris P, et al.: Pleiotrophin expression and role in physiological angiogenesis in vivo: potential involvement of nucleolin. Vasc Cell 2012, 4:4. BioMed Central Full Text
• [22]Xu K, LaManna JC: Chronic hypoxia and the cerebral circulation. J Appl Physiol 2006, 100(2):725-30.
• [23]Dore-Duffy P, Balabanov R, Beaumont T, Hritz MA, Harik SI, LaManna JC: Endothelial activation following prolonged hypobaric hypoxia. Microvasc Res 1999, 57(2):75-85.
• [24]Dore-Duffy P, Balabanov R, Beaumont T, Katar M: The CNS pericyte response to low oxygen: early synthesis of cyclopentenone prostaglandins of the J-series. Microvasc Res 2005, 69(1–2):79-88.
• [25]Dore-Duffy P, Wencel M, Katyshev V, Cleary K: Chronic mild hypoxia ameliorates chronic inflammatory activity in myelin oligodendrocyte glycoprotein (MOG) peptide induced experimental autoimmune encephalomyelitis (EAE). Adv Exp Med Biol 2011, 701:165-73.
• [26]Esen N, Blakely PK, Rainey-Barger EK, Irani DN: Complexity of the microglial activation pathways that drive innate host responses during lethal alphavirus encephalitis in mice. ASN Neuro 2012, 4(4):207-21.
• [27]Varia MA, Calkins-Adams DP, Rinker LH, Kennedy AS, Novotny DB, Fowler WC Jr, et al.: Pimonidazole: a novel hypoxia marker for complementary study of tumor hypoxia and cell proliferation in cervical carcinoma. Gynecol Oncol 1998, 71(2):270-7.
• [28]Selvaraj RK, Geiger TL: Mitigation of experimental allergic encephalomyelitis by TGF-beta induced Foxp3+ regulatory T lymphocytes through the induction of anergy and infectious tolerance. J Immunol 2008, 180(5):2830-8.
• [29]Trandem K, Anghelina D, Zhao J, Perlman S: Regulatory T cells inhibit T cell proliferation and decrease demyelination in mice chronically infected with a coronavirus. J Immunol 2010, 184(8):4391-400.
• [30]Dziurla R, Gaber T, Fangradt M, Hahne M, Tripmacher R, Kolar P, et al.: Effects of hypoxia and/or lack of glucose on cellular energy metabolism and cytokine production in stimulated human CD4+ T lymphocytes. Immunol Lett 2010, 131(1):97-105.
• [31]Dace DS, Khan AA, Kelly J, Apte RS: Interleukin-10 promotes pathological angiogenesis by regulating macrophage response to hypoxia during development. PLoS One 2008, 3(10):e3381.
• [32]Apte RS, Richter J, Herndon J, Ferguson TA: Macrophages inhibit neovascularization in a murine model of age-related macular degeneration. PLoS Med 2006, 3(8):e310.
• [33]Huang WX, Huang P, Link H, Hillert J: Cytokine analysis in multiple sclerosis by competitive RT - PCR: a decreased expression of IL-10 and an increased expression of TNF-alpha in chronic progression. Mult Scler 1999, 5(5):342-8.
• [34]Rubenstein JL, Wong VS, Kadoch C, Gao HX, Barajas R, Chen L, et al.: CXCL13 plus interleukin 10 is highly specific for the diagnosis of CNS lymphoma. Blood 2013, 121(23):4740-8.
• [35]Cannella B, Gao YL, Brosnan C, Raine CS: IL-10 fails to abrogate experimental autoimmune encephalomyelitis. J Neurosci Res 1996, 45(6):735-46.
• [36]Festa ED, Hankiewicz K, Kim S, Skurnick J, Wolansky LJ, Cook SD, et al.: Serum levels of CXCL13 are elevated in active multiple sclerosis. Mult Scler 2009, 15(11):1271-9.
• [37]Kowarik MC, Cepok S, Sellner J, Grummel V, Weber MS, Korn T, et al.: CXCL13 is the major determinant for B cell recruitment to the CSF during neuroinflammation. J Neuroinflammation 2012, 9:93. BioMed Central Full Text
• [38]Bagaeva LV, Rao P, Powers JM, Segal BM: CXC chemokine ligand 13 plays a role in experimental autoimmune encephalomyelitis. J Immunol 2006, 176(12):7676-85.
• [39]Rainey-Barger EK, Rumble JM, Lalor SJ, Esen N, Segal BM, Irani DN: The lymphoid chemokine, CXCL13, is dispensable for the initial recruitment of B cells to the acutely inflamed central nervous system. Brain Behav Immun 2011, 25(5):922-31.
• [40]Gaupp S, Pitt D, Kuziel WA, Cannella B, Raine CS: Experimental autoimmune encephalomyelitis (EAE) in CCR2(−/−) mice: susceptibility in multiple strains. Am J Pathol 2003, 162(1):139-50.
• [41]Schmitt C, Strazielle N, Ghersi-Egea JF: Brain leukocyte infiltration initiated by peripheral inflammation or experimental autoimmune encephalomyelitis occurs through pathways connected to the CSF-filled compartments of the forebrain and midbrain. J Neuroinflammation 2012, 9:187. BioMed Central Full Text
• [42]Yamasaki R, Lu H, Butovsky O, Ohno N, Rietsch AM, Cialic R, et al.: Differential roles of microglia and monocytes in the inflamed central nervous system. J Exp Med 2014, 211(8):1533-49.
• [43]LaManna JC, Chavez JC, Pichiule P: Structural and functional adaptation to hypoxia in the rat brain. J Exp Biol 2004, 207(Pt 18):3163-9.
• [44]Nilsson M, Heymach JV: Vascular endothelial growth factor (VEGF) pathway. J Thorac Oncol 2006, 1(8):768-70.
• [45]Mengozzi M, Cervellini I, Bigini P, Martone S, Biondi A, Pedotti R, et al.: Endogenous erythropoietin as part of the cytokine network in the pathogenesis of experimental autoimmune encephalomyelitis. Mol Med 2008, 14(11–12):682-8.
• [46]Pan F, Barbi J, Pardoll DM: Hypoxia-inducible factor 1: a link between metabolism and T cell differentiation and a potential therapeutic target. Oncoimmunology 2012, 1(4):510-5.
• [47]Colgan SP, Taylor CT: Hypoxia: an alarm signal during intestinal inflammation. Nat Rev Gastroenterol Hepatol 2010, 7(5):281-7.
• [48]McNamee EN, Korns Johnson D, Homann D, Clambey ET: Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function. Immunol Res 2012.
• [49]Davies AL, Desai RA, Bloomfield PS, McIntosh PR, Chapple KJ, Linington C, et al.: Neurological deficits caused by tissue hypoxia in neuroinflammatory disease. Ann Neurol 2013, 74(6):815-25.
• [50]Austin MA, Wills KE, Blizzard L, Walters EH, Wood-Baker R: Effect of high flow oxygen on mortality in chronic obstructive pulmonary disease patients in prehospital setting: randomised controlled trial. BMJ 2010, 341:c5462.
• [51]Barbi J, Pardoll D, Pan F: Metabolic control of the Treg/Th17 axis. Immunol Rev 2013, 252(1):52-77.
• [52]Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, et al.: HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 2011, 208(7):1367-76.
• [53]Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P, et al.: Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci U S A 2012, 109(41):E2784-93.
• [54]Nakamura H, Makino Y, Okamoto K, Poellinger L, Ohnuma K, Morimoto C, et al.: TCR engagement increases hypoxia-inducible factor-1 alpha protein synthesis via rapamycin-sensitive pathway under hypoxic conditions in human peripheral T cells. J Immunol 2005, 174(12):7592-9.
• [55]Nizet V, Johnson RS: Interdependence of hypoxic and innate immune responses. Nat Rev Immunol 2009, 9(9):609-17.
• [56]Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, et al.: IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 2006, 177(1):566-73.
• [57]Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al.: IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005, 201(2):233-40.
• [58]McGeachy MJ, Stephens LA, Anderton SM: Natural recovery and protection from autoimmune encephalomyelitis: contribution of CD4+CD25+ regulatory cells within the central nervous system. J Immunol 2005, 175(5):3025-32.
• [59]Segal BM: The unwavering commitment of regulatory T cells in the suppression of autoimmune encephalomyelitis: another aspect of immune privilege in the CNS. Eur J Immunol 2012, 42(5):1102-5.
• [60]Chen L, Coleman R, Leang R, Tran H, Kopf A, Walsh Craig M et al. Human neural precursor cells promote neurologic recovery in a viral model of multiple sclerosis. Stem Cell Reports. 2014;2(6):825–37. doi:http://dx.doi.org/10.1016/j.stemcr.2014.04.005.
• [61]Ragheb S, Li Y, Simon K, VanHaerents S, Galimberti D, De Riz M, et al.: Multiple sclerosis: BAFF and CXCL13 in cerebrospinal fluid. Mult Scler 2011, 17(7):819-29.
• [62]Brettschneider J, Czerwoniak A, Senel M, Fang L, Kassubek J, Pinkhardt E, et al.: The chemokine CXCL13 is a prognostic marker in clinically isolated syndrome (CIS). PLoS One 2010, 5(8):e11986.
• [63]Alvarez E, Piccio L, Mikesell RJ, Klawiter EC, Parks BJ, Naismith RT, et al.: CXCL13 is a biomarker of inflammation in multiple sclerosis, neuromyelitis optica, and other neurological conditions. Mult Scler 2013, 19(9):1204-8.
• [64]Schreml S, Szeimies RM, Prantl L, Karrer S, Landthaler M, Babilas P: Oxygen in acute and chronic wound healing. Br J Dermatol 2010, 163(2):257-68.
• [65]Xing D, Liu L, Marti GP, Zhang X, Reinblatt M, Milner SM, et al.: Hypoxia and hypoxia-inducible factor in the burn wound. Wound repair and regeneration: official publication of the Wound Healing Society [and] the European Tissue Repair. Society 2011, 19(2):205-13.
• [66]Zampell JC, Yan A, Avraham T, Daluvoy S, Weitman ES, Mehrara BJ: HIF-1alpha coordinates lymphangiogenesis during wound healing and in response to inflammation. FASEB J 2012, 26(3):1027-39.
• [67]Hayes HB, Jayaraman A, Herrmann M, Mitchell GS, Rymer WZ, Trumbower RD: Daily intermittent hypoxia enhances walking after chronic spinal cord injury: a randomized trial. Neurology 2014, 82(2):104-13.