Skip to main content

Advertisement

SpringerLink
Log in

Differential upregulation of heme oxygenase-1 (HSP32) in glial cells after oxidative stress and in demyelinating disorders

  • Original Articles
  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Oxidative stress is implicated in the pathogenesis of demyelinating disorders and inflammatory responses. Heme oxygenase-1 (HO-1; HSP32) is a small heat shock protein (HSP) with enzymatic activity, which is inducible by oxidative stress. In this study we analyzed autopsy and biopsy brain samples of patients with multiple sclerosis (MS) and ADEM (acute disseminated leucoencephalomylits) and spinal cord lesions of mouse EAE (experimental autoimmune encephalomyelitis), which was actively induced by immunization with myelin oligodendrocyte glycoprotein (MOG35–55) peptide, for the presence of HO-1. HO-1 was observed in glial cells during different stages: (1) during acute phases of mainly inflammatory diseases (EAE and ADEM) expression of HO-1 was prominent in microglia/macrophages and astrocytes, and upregulation correlated with inflammation, and (2) in early MS lesions HO-1 was expressed in oligodendrocytes. Furthermore, in glial cell cultures, we can show that upregulation of HO-1 in oligodendrocytes was paralleled by severe morphological damage. Oligodendrocytes underwent apoptotic cell death at a concentration of hydrogen peroxide (50–200 µM) which did not affect astrocytes or microglia. Using oligodendroglial OLN-93 cells, we demonstrate that oxidative stress led to mitochondrial impairment and the disorganization of the microtubule network. Zinc protoporphyrin, an inhibitor of HO-1, augmented the cytotoxic consequences of hydrogen peroxide in OLN-93 cells. Hence, the presence of HO-1 in EAE, ADEM, and MS points to the involvement of oxidative stress and a role of HO-1 in the pathogenesis of the diseases. The data suggest that stress-induced HO-1 initially plays a protective role, while its chronic upregulation, might contribute to oligodendroglial cell death rather than providing protection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abdul-Majid, K.-B., Jirholt, J., Stadelmann, C., Stefferl, A., Kjellén, P., Wallström, E., et al. (2000). Screening of several H-2 congenic mouse strains identified H-2q mice as highly susceptible to MOG-induced EAE with minimal adjuvant requirement. Journal of Neuroimmunology, 111, 23–33.

    Article  PubMed  CAS  Google Scholar 

  • Banati, R. B., Gehrmann, J., Schubert, P., & Kreutzberg, G. W. (1993). Cytotoxicity of microglia. Glia, 7, 111–118.

    Article  PubMed  CAS  Google Scholar 

  • Bimbaum, G. (1995). Stress proteins: Their role in the normal central nervous system and in disease states, especially multiple sclerosis. Springer Seminars in Immunopathology, 17, 107–118.

    Google Scholar 

  • Bourquin, C., Iglesias, A., Berger, T., Wekerle, H., & Linington, C. (2000). Myelin oligodendrocyte glycoprotein-DNA vaccination induces antibody-mediated autoaggression in experimental autoimmune encephalomyelitis. European Journal of Immunology, 30, 3663–3671.

    Article  PubMed  CAS  Google Scholar 

  • Brosnan, C. F., Battistini, L., Gao, Y. L., & Aquino, D. A. (1996). Heat shock proteins and multiple sclerosis: A review. Journal of Neuropathology and Experimental Neurology, 55, 389–402.

    Article  PubMed  CAS  Google Scholar 

  • Brück, W., Luccinetti, C., & Lassmann, H. (2002). The pathology of primary progressive multiple sclerosis. Multiple Sclerosis, 8, 93–97.

    Article  PubMed  Google Scholar 

  • Chakrabarty, A., Emerson, M. R., & LeVine, S. M. (2003), Heme oxygenase-1 in SJL mice with experimental allergic encephalomyelitis. Multiple Sclerosis, 9, 372–381.

    Article  PubMed  CAS  Google Scholar 

  • Desagher, S., & Martinou, J. C. (2000). Mitochondria as the central control point of apoptosis. Trends in Cell Biology, 10, 369–377.

    Article  PubMed  CAS  Google Scholar 

  • Elbirt, K. K., & Bonkovsky, H. L. (1999). Heme oxygenase: Recent advances in understanding its regulation and role. Proceedings of the Association American Physicians, 111, 438–447.

    CAS  Google Scholar 

  • Elbirt, K. K., Whitmarsh, A. J., Davis, R. J., & Bonkovsky, H. L. (1998). Mechanism of sodium arsenite-mediated induction of heme oxygenase-1 in hepatoma cells. Role of mitogen-activated protein kinases. Journal of Biological Chemistry, 372, 8922–8931.

    Article  Google Scholar 

  • Emerson, R. M., & LeVine, S. M. (2000). Heme oxygenase-1 and NADPH cytochrome P450 reductases expression in experimental allergic encephalomyelitis: An expanded view of the stress response. Journal of Neurochemistry, 75, 2555–2562.

    Article  PubMed  CAS  Google Scholar 

  • Eugster, H.-P., Frei, K., Bachmann, R., Bluethmann, H., Lassmann, H., & Fontana, A. (1999). Severity of symptoms and demyelination in MOG-induced EAE depends on TNFR1. European Journal of Immunology, 29, 626–632.

    Article  PubMed  CAS  Google Scholar 

  • Fink, A. L. (1999). Chaperone-mediated protein folding. Physiological Reviews, 79, 425–449.

    PubMed  CAS  Google Scholar 

  • Goldbaum, O., & Richter-Landsberg, C. (2001). Stress proteins in oligodendrocytes: Differential effects of heat shock and oxidative stress. Journal of Neurochemistry, 78, 1233–1242.

    Article  PubMed  CAS  Google Scholar 

  • Goldbaum, O., & Richter-Landsberg, C. (2002). Activation of PP2A-like phosphatase and modulation of tau phosphorylation accompany stress-induced apoptosis in cultured oligodendrocytes. Glia, 40, 271–282.

    Article  PubMed  Google Scholar 

  • Head, M. W., & Goldman, J. E. (2000). Small heat shock proteins, the cytoskeleton and inclusion body formation. Neuropathology and Applied Neurobiology, 26, 304–312.

    Article  PubMed  CAS  Google Scholar 

  • Heneka, M. T., Sharp, A., Murphy, P., Lyons, J. A., Dumitrescu, L., & Feinstein, D. L. (2001). The heat shock response reduces myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in mice. Journal of Neurochemistry, 77, 568–579.

    Article  PubMed  CAS  Google Scholar 

  • Henningsson, R., Alm, P., Ekström, P., & Lundquist, I. (1999). Heme oxygenase and carbon monoxide: Regulatory roles in islet hormone release. A biochemical, immunohistochemical, and confocal microscopic study. Diabetes, 48, 66–76.

    Article  PubMed  CAS  Google Scholar 

  • Jelinski, S. E., Yager, J. Y., & Juurlink, B. H. J. (1999). Preferential injury of oligodendroblasts by a short hypoxic-ischemic insult. Brain Research, 815, 150–153.

    Article  PubMed  CAS  Google Scholar 

  • Johns, T. G., Kerlero, D. R., Menon, K. K., Abo, S., Gonzales, M. F., & Bernard, C. C. (1995). Myelin oligodendrocyte glycoprotein induces a demyelinating encephalomyelits resembling multiple sclerosis. Journal of Neuroimmunology, 154, 5536–5541.

    CAS  Google Scholar 

  • Kalman, B., & Leist, T. P. (2003). A mitochondrial component of neurodegeneration in multiple sclerosis. NeuroMolecular Medicine, 3, 147–157.

    Article  PubMed  CAS  Google Scholar 

  • Lassmann, H., Brück, W., & Lucchinetti, C. (2001). Heterogeneity of multiple sclerosis pathogenesis: Implications for diagnosis and therapy. Trends in Molecular Medicine, 7, 115–121.

    Article  PubMed  CAS  Google Scholar 

  • Liang, P., & MacRae, T. H. (1997). Molecular chaperones and the cytoskeleton. Journal of Cell Science, 110, 1431–1440.

    PubMed  CAS  Google Scholar 

  • Liu, Y., Tachibana, T., Dai, Y., Kondo, E., Fukuoka, T., Yamanaka, H., et al. (2002). Heme oxygenase-1 expression after spinal cord injury: The induction in activated neutrophils. Journal of Neurotrauma, 19, 479–490.

    Article  PubMed  Google Scholar 

  • Liu, Y., Zhu, B., Luo, L., Paty, D. W., & Cynader, M. S. (2001). Heme oxygenase-1 plays an important protective role in experimental autoimmune encephalomyelitis. Neuroreport, 12, 1841–1845.

    Article  PubMed  CAS  Google Scholar 

  • Ludwin, S. K. (1997). The pathobiology of the oligodendrocyte. Journal of Neuropathology and Experimental Neurology, 56, 111–124.

    Article  PubMed  CAS  Google Scholar 

  • Malipiero, U., Frei, K., Spanaus, K.-S., Agresti, C., Lassmann, H., Hahne, M., et al. (1997). Myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis is chronic/relapsing in perforin knockout mice, but monophasic in Fas- and Fas ligand-deficient lpr and gld mice. European Journal of Immunology, 27, 3151–3160.

    Article  PubMed  CAS  Google Scholar 

  • McMorris, F. A., Miller, S. L., Pleasure, D., & Abramsky, O. (1981). Expression of biochemical properties of oligodendrocytes in oligodendrocyte×glioma cell hybrids proliferating in vitro. Experimental Cell Research, 133, 395–404.

    Article  PubMed  CAS  Google Scholar 

  • Mendel, I., Kerlero de Rosbo, N., & Ben-Nun, A. (1995). A myelin oligodendrocyte glycoprotein peptide induces typical chronic experimental autoimmune encephalomyelitis in H-2b mice: Fine specificity and T cell receptor Vβ expression of encephalitogenic T cells. European Journal of Immunology, 25, 1951–1959.

    Article  PubMed  CAS  Google Scholar 

  • Minghetti, L., Polazzi, E., Nicolini, A., & Levi, G. (1998). Opposite regulation of prostaglandin E2 synthesis by transforming growth factor-beta1 and interleukin 10 in activated microglial cultures. Journal of Neuroimmunology, 82, 31–39.

    Article  PubMed  CAS  Google Scholar 

  • Mronga, T., Stahnke, T., Goldbaum, O., & Richter-Landsberg, C. (2004). Mitochondrial pathway is involved in hydrogen peroxide induced apoptotic cell death of oligodendrocytes. Glia, 46, 446–455.

    Article  PubMed  Google Scholar 

  • Nacken, W., Roth, J., Sorg, C., & Kerkhoff, C. (2003). S100A9/S100A8: Myeloid representatives of the S100 protein family as prominent players in innate immunity. Microscopy Research and Technique, 60, 569–580.

    Article  PubMed  CAS  Google Scholar 

  • Neuhoff, V., Philipp, K., Zimmer, H. G., & Mesecke, S. (1979). A simple, versatile, sensitive and volume-independent method for quantitative protein determination which is independent of other external influences. Hoppe-Seyler’s Zeitschrift für Physiologische Chemie, 360, 1657–1670.

    PubMed  CAS  Google Scholar 

  • Richter-Landsberg, C. (2001). Organization and functional roles of the cytoskeleton in oligodendrocytes. Microscopy Research and Technique, 52, 628–636.

    Article  PubMed  CAS  Google Scholar 

  • Richter-Landsberg, C., & Goldbaum, O. (2003). Stress responses in neural cells: Functional roles in health and disease. Cellular and Molecular Life Sciences, 60, 337–349.

    Article  PubMed  CAS  Google Scholar 

  • Richter-Landsberg, C., & Heinrich, M. (1996). OLN-93: A new permanent oligodendroglia cell line derived from primary rat brain glial cultures. Journal of Neuroscience Research, 45, 161–173.

    Article  PubMed  CAS  Google Scholar 

  • Samali, A., & Cotter, T. G. (1996). Heat shock proteins increase resistance to apoptosis. Experimental Cell Research, 223, 163–170.

    Article  PubMed  CAS  Google Scholar 

  • Schipper, H. M. (2000). Heme oxygenase-1: Role in brain aging and neurodegeneration. Experimental Gerontology, 35, 821–830.

    Article  PubMed  CAS  Google Scholar 

  • Schipper, H. M. (2004). Heme oxygenase-1: Transducer of pathological brain iron sequestration under oxidative stress. Annals of the New York Academy of Sciences, 1012, 84–93.

    Article  PubMed  CAS  Google Scholar 

  • Schluesener, H. J., & Seid, K. (2000). Heme oxygenase-1 in lesions of rat experimental autoimmune encephalomyelitis and neuritis. Journal of Neuroimmunology, 110, 114–120.

    Article  PubMed  CAS  Google Scholar 

  • Sharp, F. R., Massa, S. M., & Swanson, R. A. (1999). Heat shock protein protection. Trends in Neurosciences, 22, 97–99.

    Article  PubMed  CAS  Google Scholar 

  • Song, W., Su, H., Song, S., Paudel, H. K., & Schipper, H. M. (2006). Over-expression of heme oxygenase-1 promotes oxidative mitochondrial damage in rat astroglia. Journal of Cellular Physiology, 206, 655–663.

    Article  PubMed  CAS  Google Scholar 

  • Sriram, S., & Rodriguez, M. (1997). Indictment of the microglia as the villain in multiple sclerosis. Neurology, 48, 464–470.

    PubMed  CAS  Google Scholar 

  • Steinmann, L., Martin, R., Bernard, C., Conlon, P., & Oksenberg, J. R. (2002). Multiple sclerosis: Deeper understanding of its pathogenesis reveals new targets for therapy. Annual Review of Neuroscience, 25, 491–505.

    Article  CAS  Google Scholar 

  • Storch, M. K., Stefferl, A., Brehm, U., Weissert, R., Wallstrom, E., Kerschensteiner, M., et al. (1998). Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology. Brain Pathology, 8, 681–695.

    Article  PubMed  CAS  Google Scholar 

  • van Noort, J. M., Van Sechel, A. C., Bajramovic, J. J., El Quagmiri, M., Polman, C. H., Lassmann, H., et al. (1995). The small heat shock protein αB-crystallin as candidate autoantigen in multiple sclerosis. Nature, 375, 798–801.

    Article  PubMed  Google Scholar 

  • Vollgraf, U., Wegner, M., & Richter-Landsberg, C. (1999). Activation of AP-1 and NF-kappaB transcription factors is involved in hydrogen peroxide-induced apoptotic cell death of oligodendrocytes. Journal of Neurochemistry, 73, 2501–2509.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biology, Molecular Neurobiology, University of Oldenburg, POB 2503, D-26111, Oldenburg, Germany

    T. Stahnke & C. Richter-Landsberg

  2. Institute of Neuropathology, University of Göttingen, Göttingen, Germany

    C. Stadelmann, A. Netzler & W. Brück

Authors
  1. T. Stahnke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Richter-Landsberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Stadelmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Netzler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W. Brück
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Richter-Landsberg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stahnke, T., Richter-Landsberg, C., Stadelmann, C. et al. Differential upregulation of heme oxygenase-1 (HSP32) in glial cells after oxidative stress and in demyelinating disorders. J Mol Neurosci 32, 25–37 (2007). https://doi.org/10.1007/s12031-007-0005-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-007-0005-8

Keywords

Search

Navigation