Advertisement

Journal of Molecular Neuroscience

, Volume 67, Issue 2, pp 265–275 | Cite as

Mitochondrial Impairment in Oligodendroglial Cells Induces Cytokine Expression and Signaling

  • Miriam ScheldEmail author
  • Athanassios Fragoulis
  • Stella Nyamoya
  • Adib Zendedel
  • Bernd Denecke
  • Barbara Krauspe
  • Nico Teske
  • Markus Kipp
  • Cordian Beyer
  • Tim Clarner
Article
  • 140 Downloads

Abstract

Widespread inflammatory lesions within the central nervous system grey and white matter are major hallmarks of multiple sclerosis. The development of full-blown demyelinating multiple sclerosis lesions might be preceded by preactive lesions which are characterized by focal microglia activation in close spatial relation to apoptotic oligodendrocytes. In this study, we investigated the expression of signaling molecules of oligodendrocytes that might be involved in initial microglia activation during preactive lesion formation. Sodium azide was used to trigger mitochondrial impairment and cellular stress in oligodendroglial cells in vitro. Among various chemokines and cytokines, IL6 was identified as a possible oligodendroglial cell-derived signaling molecule in response to cellular stress. Relevance of this finding for lesion development was further explored in the cuprizone model by applying short-term cuprizone feeding (2–4 days) on male C57BL/6 mice and subsequent analysis of gene expression, in situ hybridization and histology. Additionally, we analyzed the possible signaling of stressed oligodendroglial cells in vitro as well as in the cuprizone mouse model. In vitro, conditioned medium of stressed oligodendroglial cells triggered the activation of microglia cells. In cuprizone-fed animals, IL6 expression in oligodendrocytes was found in close vicinity of activated microglia cells. Taken together, our data support the view that stressed oligodendrocytes have the potential to activate microglia cells through a specific cocktail of chemokines and cytokines among IL6. Further studies will have to identify the temporal activation pattern of these signaling molecules, their cellular sources, and impact on neuroinflammation.

Keywords

Oligodendrocytes Cytokines Multiple sclerosis Preactive lesions IL6 Microglia 

Notes

Acknowledgements

The excellent support by Helga Helten, Petra Ibold and Uta Zahn is appreciated. We thank Prof. Dr. Reinhard Windoffer and Dr. Volker Buck for their assistance with confocal microscopy and PD Dr. Claudia Krusche for technical support.

Funding Information

Grant sponsor: This study was funded by the START program of the medical faculty of the RWTH Aachen University (M.S.).

Compliance with ethical standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12031_2018_1236_MOESM1_ESM.pdf (1.5 mb)
ESM 1 (A) Schematic illustration of the in vitro experimental setup for oligodendroglial cell stimulation and subsequent microglia stimulation with OCM. Oligodendroglial cells (OLN93) were stressed with 10 mM SA for 24 h, medium changed and incubated for 24 h with or without SA to produce OCM-vehicle and OCM-SA, respectively. OCM was then used to stimulate microglia cells for 6 h. (B) Time-line diagram of the 2-d cuprizone feeding in vivo experiments. (C) Signal specificity was validated by incubating slices with the respective secondary antibody without pre-incubation with the first antibody. Results for IL6 and OLIG2 negative controls are shown. Note that no signal was found within the examined tissue regions for any secondary antibody (scale bars 50 μm). Cross reactivity of secondary antibodies with each other or the false primary antibody was additionally excluded (data not shown). (D) Double labeling of IL6 with GFAP and IBA-1 (scale bars 10 μm) shows that also other glial cells than oligodendrocytes are possible sources of IL6 after 2 d cuprizone intoxication. No signal was found in the wildtype negative control (lower row) (scale bars 20 μm). (E) No morphological changes such as an increase in the number of bipolar cells or an increased arborization were found in OCM-SA-stimulated compared to OCM-Veh-stimulated BV2 microglia cells. (F) Shows the gene expression results of arginase 1 and Nos2 (BoxCox-Y transformed) of IL6-stimulated microglia cells (four culture wells, one experiment). LPS stimulation served as a positive control for Nos2 induction. *p < 0.05, vehicle, up H2O (PDF 1494 kb)

References

  1. Balabanov R, Strand K, Goswami R, McMahon E, Begolka W, Miller SD, Popko B (2007) Interferon-gamma-oligodendrocyte interactions in the regulation of experimental autoimmune encephalomyelitis. J Neurosci 27(8):2013–2024Google Scholar
  2. Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 55(4):458–468Google Scholar
  3. Bennett MC, Mlady GW, Kwon YH, Rose GM (1996) Chronic in vivo sodium azide infusion induces selective and stable inhibition of cytochrome c oxidase. J Neurochem 66(6):2606–2611Google Scholar
  4. Blasi E, Barluzzi R, Bocchini V, Mazzolla R, Bistoni F (1990) Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol 27(2-3):229–237Google Scholar
  5. Bonaterra GA, Zugel S, Thogersen J, Walter SA, Haberkorn U, Strelau J, Kinscherf R (2012) Growth differentiation factor-15 deficiency inhibits atherosclerosis progression by regulating interleukin-6-dependent inflammatory response to vascular injury. J Am Heart Assoc 1(6):e002550PubMedCentralGoogle Scholar
  6. Cannella B, Raine CS (2004) Multiple sclerosis: cytokine receptors on oligodendrocytes predict innate regulation. Ann Neurol 55(1):46–57Google Scholar
  7. Chabas D, Baranzini SE, Mitchell D, Bernard CC, Rittling SR, Denhardt DT, Sobel RA, Lock C, Karpuj M, Pedotti R, Heller R, Oksenberg JR, Steinman L (2001) The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294(5547):1731–1735Google Scholar
  8. Chen M, Chen G, Nie H, Zhang X, Niu X, Zang YC, Skinner SM, Zhang JZ, Killian JM, Hong J (2009) Regulatory effects of IFN-beta on production of osteopontin and IL-17 by CD4+ T Cells in MS. Eur J Immunol 39(9):2525–2536Google Scholar
  9. Clarner T, Diederichs F, Berger K, Denecke B, Gan L, van der Valk P, Beyer C, Amor S, Kipp M (2012) Myelin debris regulates inflammatory responses in an experimental demyelination animal model and multiple sclerosis lesions. Glia 60(10):1468–1480Google Scholar
  10. Clarner T, Janssen K, Nellessen L, Stangel M, Skripuletz T, Krauspe B, Hess FM, Denecke B, Beutner C, Linnartz-Gerlach B, Neumann H, Vallieres L, Amor S, Ohl K, Tenbrock K, Beyer C, Kipp M (2015) CXCL10 triggers early microglial activation in the cuprizone model. J Immunol 194(7):3400–3413Google Scholar
  11. Damas P, Ledoux D, Nys M, Vrindts Y, De Groote D, Franchimont P, Lamy M (1992) Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg 215(4):356–362PubMedCentralGoogle Scholar
  12. De Groot CJ, Bergers E, Kamphorst W, Ravid R, Polman CH, Barkhof F, van der Valk P (2001) Post-mortem MRI-guided sampling of multiple sclerosis brain lesions: increased yield of active demyelinating and (p)reactive lesions. Brain 124(Pt 8):1635–1645Google Scholar
  13. Draheim T, Liessem A, Scheld M, Wilms F, Weissflog M, Denecke B, Kensler TW, Zendedel A, Beyer C, Kipp M, Wruck CJ, Fragoulis A, Clarner T (2016) Activation of the astrocytic Nrf2/ARE system ameliorates the formation of demyelinating lesions in a multiple sclerosis animal model. Glia 64(12):2219–2230Google Scholar
  14. Edagawa M, Kawauchi J, Hirata M, Goshima H, Inoue M, Okamoto T, Murakami A, Maehara Y, Kitajima S (2014) Role of activating transcription factor 3 (ATF3) in endoplasmic reticulum (ER) stress-induced sensitization of p53-deficient human colon cancer cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis through up-regulation of death receptor 5 (DR5) by zerumbone and celecoxib. J Biol Chem 289(31):21544–21561PubMedCentralGoogle Scholar
  15. Elmore MR, Najafi AR, Koike MA, Dagher NN, Spangenberg EE, Rice RA, Kitazawa M, Matusow B, Nguyen H, West BL, Green KN (2014) Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82(2):380–397PubMedCentralGoogle Scholar
  16. Gay FW, Drye TJ, Dick GW, Esiri MM (1997) The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis. Identification and characterization of the primary demyelinating lesion. Brain 120(Pt 8):1461–1483Google Scholar
  17. Gehrmann J, Matsumoto Y, Kreutzberg GW (1995) Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 20(3):269–287Google Scholar
  18. Hirota H, Kiyama H, Kishimoto T, Taga T (1996) Accelerated nerve regeneration in mice by upregulated expression of interleukin (IL) 6 and IL-6 receptor after trauma. J Exp Med 183(6):2627–2634Google Scholar
  19. Hollensworth SB, Shen C, Sim JE, Spitz DR, Wilson GL, LeDoux SP (2000) Glial cell type-specific responses to menadione-induced oxidative stress. Free Radic Biol Med 28(8):1161–1174Google Scholar
  20. Holmberg KH, Patterson PH (2006) Leukemia inhibitory factor is a key regulator of astrocytic, microglial and neuronal responses in a low-dose pilocarpine injury model. Brain Res 1075(1):26–35Google Scholar
  21. Jiang J, Wen W, Sachdev PS (2016) Macrophage inhibitory cytokine-1/growth differentiation factor 15 as a marker of cognitive ageing and dementia. Curr Opin Psychiatry 29(2):181–186Google Scholar
  22. Kempf T, Eden M, Strelau J, Naguib M, Willenbockel C, Tongers J, Heineke J, Kotlarz D, Xu J, Molkentin JD, Niessen HW, Drexler H, Wollert KC (2006) The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ Res 98(3):351–360Google Scholar
  23. Kempuraj D, Thangavel R, Natteru PA, Selvakumar GP, Saeed D, Zahoor H, Zaheer S, Iyer SS, Zaheer A (2016) Neuroinflammation induces neurodegeneration. J Neurol Neurosurg Spine 1(1)Google Scholar
  24. Krauspe BM, Dreher W, Beyer C, Baumgartner W, Denecke B, Janssen K, Langhans CD, Clarner T, Kipp M (2015) Short-term cuprizone feeding verifies N-acetylaspartate quantification as a marker of neurodegeneration. J Mol Neurosci 55(3):733–748Google Scholar
  25. Kummer JA, Broekhuizen R, Everett H, Agostini L, Kuijk L, Martinon F, van Bruggen R, Tschopp J (2007) Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response. J Histochem Cytochem 55(5):443–452Google Scholar
  26. Linnane AW, Marzuki S, Ozawa T, Tanaka M (1989) Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 1(8639):642–645Google Scholar
  27. Mahad D, Lassmann H, Turnbull D (2008) Review: mitochondria and disease progression in multiple sclerosis. Neuropathol Appl Neurobiol 34(6):577–589PubMedCentralGoogle Scholar
  28. Maiti AK, Sharba S, Navabi N, Forsman H, Fernandez HR, Lindén SK (2015) IL-4 protects the mitochondria against TNFα and IFNγ induced insult during clearance of infection with citrobacter rodentium and Escherichia coli. Scientific Reports 5:15434PubMedCentralGoogle Scholar
  29. Mao P, Reddy PH (2010) Is multiple sclerosis a mitochondrial disease? Biochimica et biophysica acta 1802(1):66–79Google Scholar
  30. Marik C, Felts PA, Bauer J, Lassmann H, Smith KJ (2007) Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain 130(Pt 11):2800–2815PubMedCentralGoogle Scholar
  31. Matsumoto J, Dohgu S, Takata F, Machida T, Bolukbasi Hatip FF, Hatip-Al-Khatib I, Yamauchi A, Kataoka Y (2018) TNF-alpha-sensitive brain pericytes activate microglia by releasing IL-6 through cooperation between IkappaB-NFkappaB and JAK-STAT3 pathways. Brain Res 1692:34–44Google Scholar
  32. Merabova N, Kaminski R, Krynska B, Amini S, Khalili K, Darbinyan A (2012) JCV agnoprotein-induced reduction in CXCL5/LIX secretion by oligodendrocytes is associated with activation of apoptotic signaling in neurons. J Cell Physiol 227(8):3119–3127PubMedCentralGoogle Scholar
  33. Mochida S, Yoshimoto T, Mimura S, Inao M, Matsui A, Ohno A, Koh H, Saitoh E, Nagoshi S, Fujiwara K (2004) Transgenic mice expressing osteopontin in hepatocytes as a model of autoimmune hepatitis. Biochem Biophys Res Commun 317(1):114–120Google Scholar
  34. Moyon S, Dubessy AL, Aigrot MS, Trotter M, Huang JK, Dauphinot L, Potier MC, Kerninon C, Melik Parsadaniantz S, Franklin RJ, Lubetzki C (2015) Demyelination causes adult CNS progenitors to revert to an immature state and express immune cues that support their migration. J Neurosci 35(1):4–20Google Scholar
  35. Okamura RM, Lebkowski J, Au M, Priest CA, Denham J, Majumdar AS (2007) Immunological properties of human embryonic stem cell-derived oligodendrocyte progenitor cells. J Neuroimmunol 192(1-2):134–144Google Scholar
  36. Perry VH, Andersson PB, Gordon S (1993) Macrophages and inflammation in the central nervous system. Trends Neurosci 16(7):268–273Google Scholar
  37. Petkovic F, Campbell IL, Gonzalez B, Castellano B (2017) Reduced cuprizone-induced cerebellar demyelination in mice with astrocyte-targeted production of IL-6 is associated with chronically activated, but less responsive microglia. J Neuroimmunol 310:97–102Google Scholar
  38. Puthalakath H, O'Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, Hughes PD, Michalak EM, McKimm-Breschkin J, Motoyama N, Gotoh T, Akira S, Bouillet P, Strasser A (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129(7):1337–1349Google Scholar
  39. Ramesh G, Benge S, Pahar B, Philipp MT (2012) A possible role for inflammation in mediating apoptosis of oligodendrocytes as induced by the Lyme disease spirochete Borrelia burgdorferi. J Neuroinflammation 9:72PubMedCentralGoogle Scholar
  40. Richter-Landsberg C, Heinrich M (1996) OLN-93: a new permanent oligodendroglia cell line derived from primary rat brain glial cultures. J Neurosci Res 45(2):161–173Google Scholar
  41. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH (2000) Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101(15):1767–1772Google Scholar
  42. Ruther BJ, Scheld M, Dreymueller D, Clarner T, Kress E, Brandenburg LO, Swartenbroekx T, Hoornaert C, Ponsaerts P, Fallier-Becker P, Beyer C, Rohr SO, Schmitz C, Chrzanowski U, Hochstrasser T, Nyamoya S, Kipp M (2017) Combination of cuprizone and experimental autoimmune encephalomyelitis to study inflammatory brain lesion formation and progression. Glia 65(12):1900–1913Google Scholar
  43. Rutkowski DT, Arnold SM, Miller CN, Wu J, Li J, Gunnison KM, Mori K, Sadighi Akha AA, Raden D, Kaufman RJ (2006) Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol 4(11):e374PubMedCentralGoogle Scholar
  44. Scheld M, Ruther BJ, Grosse-Veldmann R, Ohl K, Tenbrock K, Dreymuller D, Fallier-Becker P, Zendedel A, Beyer C, Clarner T, Kipp M (2016) Neurodegeneration triggers peripheral immune cell recruitment into the forebrain. J Neurosci 36(4):1410–1415Google Scholar
  45. Schlittenhardt D, Schmiedt W, Bonaterra GA, Metz J, Kinscherf R (2005) Colocalization of oxidized low-density lipoprotein, caspase-3, cyclooxygenase-2, and macrophage migration inhibitory factor in arteriosclerotic human carotid arteries. Cell Tissue Res 322(3):425–435Google Scholar
  46. Schonrock LM, Gawlowski G, Bruck W (2000) Interleukin-6 expression in human multiple sclerosis lesions. Neurosci Lett 294(1):45–48Google Scholar
  47. Seino Y, Ikeda U, Ikeda M, Yamamoto K, Misawa Y, Hasegawa T, Kano S, Shimada K (1994) Interleukin 6 gene transcripts are expressed in human atherosclerotic lesions. Cytokine 6(1):87–91Google Scholar
  48. Selvaraju R, Bernasconi L, Losberger C, Graber P, Kadi L, Avellana-Adalid V, Picard-Riera N, Baron Van Evercooren A, Cirillo R, Kosco-Vilbois M, Feger G, Papoian R, Boschert U (2004) Osteopontin is upregulated during in vivo demyelination and remyelination and enhances myelin formation in vitro. Mol Cell Neurosci 25(4):707–721Google Scholar
  49. Škuljec J, Sun H, Pul R, Bénardais K, Ragancokova D, Moharregh-Khiabani D, Kotsiari A, Trebst C, Stangel M (2011) CCL5 induces a pro-inflammatory profile in microglia in vitro. Cellular Immunology 270(2):164–171Google Scholar
  50. Su K, Bourdette D, Forte M (2013) Mitochondrial dysfunction and neurodegeneration in multiple sclerosis. Front Physiol 4:169PubMedCentralGoogle Scholar
  51. Sugiura S, Lahav R, Han J, Kou SY, Banner LR, de Pablo F, Patterson PH (2000) Leukaemia inhibitory factor is required for normal inflammatory responses to injury in the peripheral and central nervous systems in vivo and is chemotactic for macrophages in vitro. Eur J Neurosci 12(2):457–466Google Scholar
  52. Swardfager W, Lanctot K, Rothenburg L, Wong A, Cappell J, Herrmann N (2010) A meta-analysis of cytokines in Alzheimer's disease. Biol Psychiatry 68(10):930–941Google Scholar
  53. Teske N, Liessem A, Fischbach F, Clarner T, Beyer C, Wruck C, Fragoulis A, Tauber SC, Victor M, Kipp M (2018) Chemical hypoxia-induced integrated stress response activation in oligodendrocytes is mediated by the transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2). J Neurochem 144(3):285–301Google Scholar
  54. Tezuka T, Tamura M, Kondo MA, Sakaue M, Okada K, Takemoto K, Fukunari A, Miwa K, Ohzeki H, Kano S, Yasumatsu H, Sawa A, Kajii Y (2013) Cuprizone short-term exposure: astrocytic IL-6 activation and behavioral changes relevant to psychosis. Neurobiol Dis 59:63–68PubMedCentralGoogle Scholar
  55. Tsui KH, Chang YL, Feng TH, Chung LC, Lee TY, Chang PL, Juang HH (2012) Growth differentiation factor-15 upregulates interleukin-6 to promote tumorigenesis of prostate carcinoma PC-3 cells. J Mol Endocrinol 49(2):153–163Google Scholar
  56. Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, Fugger L (2008) Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 172(1):146–155PubMedCentralGoogle Scholar
  57. van der Valk P, Amor S (2009) Preactive lesions in multiple sclerosis. Curr Opin Neurol 22(3):207–213Google Scholar
  58. Wang CH, Wu SB, Wu YT, Wei YH (2013) Oxidative stress response elicited by mitochondrial dysfunction: implication in the pathophysiology of aging. Exp Biol Med (Maywood) 238(5):450–460Google Scholar
  59. Wruck CJ, Streetz K, Pavic G, Gotz ME, Tohidnezhad M, Brandenburg LO, Varoga D, Eickelberg O, Herdegen T, Trautwein C, Cha K, Kan YW, Pufe T (2011) Nrf2 induces interleukin-6 (IL-6) expression via an antioxidant response element within the IL-6 promoter. J Biol Chem 286(6):4493–4499Google Scholar
  60. Wuerfel J, Bellmann-Strobl J, Brunecker P, Aktas O, McFarland H, Villringer A, Zipp F (2004) Changes in cerebral perfusion precede plaque formation in multiple sclerosis: a longitudinal perfusion MRI study. Brain 127(Pt 1):111–119Google Scholar
  61. Yang P, Wen H, Ou S, Cui J, Fan D (2012) IL-6 promotes regeneration and functional recovery after cortical spinal tract injury by reactivating intrinsic growth program of neurons and enhancing synapse formation. Exp Neurol 236(1):19–27Google Scholar
  62. Yang R, Lirussi D, Thornton TM, Jelley-Gibbs DM, Diehl SA, Case LK, Madesh M, Taatjes DJ, Teuscher C, Haynes L, Rincon M (2015) Mitochondrial Ca(2)(+) and membrane potential, an alternative pathway for Interleukin 6 to regulate CD4 cell effector function. Elife 4Google Scholar
  63. Yumoto K, Ishijima M, Rittling SR, Tsuji K, Tsuchiya Y, Kon S, Nifuji A, Uede T, Denhardt DT, Noda M (2002) Osteopontin deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice. Proc Natl Acad Sci U S A 99(7):4556–4561PubMedCentralGoogle Scholar
  64. Zeis T, Probst A, Steck AJ, Stadelmann C, Bruck W, Schaeren-Wiemers N (2009) Molecular changes in white matter adjacent to an active demyelinating lesion in early multiple sclerosis. Brain Pathol 19(3):459–466Google Scholar
  65. Zhang X, Tachibana S, Wang H, Hisada M, Williams GM, Gao B, Sun Z (2010) Interleukin-6 is an important mediator for mitochondrial DNA repair after alcoholic liver injury in mice. Hepatology 52(6):2137–2147PubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of Neuroanatomy, Faculty of MedicineRWTH Aachen UniversityAachenGermany
  2. 2.Department of Anatomy and Cell Biology, Faculty of MedicineRWTH Aachen UniversityAachenGermany
  3. 3.Department of Neuroanatomy, Faculty of MedicineLudwig-Maximilians-University of MunichMunichGermany
  4. 4.IZKF Genomics Facility, Interdisciplinary Center for Clinical ResearchRWTH Aachen UniversityAachenGermany
  5. 5.Clinic for Gynaecology and Obstetrics, Faculty of MedicineRWTH Aachen UniversityAachenGermany
  6. 6.Institute of Anatomy, Faculty of MedicineUniversity of RostockRostockGermany

Personalised recommendations