Mechanisms Involved in the Modulation of Astroglial Resistance to Oxidative Stress Induced by Activated Microglia: Antioxidative Systems, Peroxide Elimination, Radical Generation, Lipid Peroxidation
- 222 Downloads
Microglia and astrocytes are the cellular key players in many neurological disorders associated with oxidative stress and neuroinflammation. Previously, we have shown that microglia activated by lipopolysaccharides (LPS) induce the expression of antioxidative enzymes in astrocytes and render them more resistant to hydrogen peroxide (H2O2). In this study, we examined the mechanisms involved with respect to the cellular action of different peroxides, the ability to detoxify peroxides, and the status of further antioxidative systems. Astrocytes were treated for 3 days with medium conditioned by purified quiescent (microglia-conditioned medium, MCM[−]) or LPS-activated (MCM[+]) microglia. MCM[+] reduced the cytotoxicity of the organic cumene hydroperoxide in addition to that of H2O2. Increased peroxide resistance was not accompanied by an improved ability of astrocytes to remove H2O2 or an increased expression/activity of peroxide eliminating antioxidative enzymes. Neither peroxide-induced radical generation nor lipid peroxidation were selectively affected in MCM[+] treated astrocytes. The glutathione content of peroxide resistant astrocytes, however, was increased and superoxide dismutase and heme oxygenase were found to be upregulated. These changes are likely to contribute to the higher peroxide resistance of MCM[+] treated astrocytes by improving their ability to detoxify reactive oxygen radicals and oxidation products. For C6 astroglioma cells a protective effect of microglia-derived factors could not be observed, underlining the difference of primary cells and cell lines concerning their mechanisms of oxidative stress resistance. Our results indicate the importance of microglial–astroglial cell interactions during neuroinflammatory processes.
KeywordsGlial cell interactions Inflammation Gliosis Antioxidative enzymes Glutathione
The authors thank Monika Grell and Rosemarie Sprang for their excellent technical assistance during these studies, and Jobst Sievers and Ralph Lucius for providing laboratory facilities.
- Bordet R, Deplanque D, Maboudou P, Puisieux F, Pu Q, Robin E, Martin A, Bastide M, Leys D, Lhermitte M, Dupuis B (2000) Increase in endogenous brain superoxide dismutase as a potential mechanism of lipopolysaccharide-induced brain ischemic tolerance. J Cereb Blood Flow Metab 20(8):1190–1196CrossRefPubMedGoogle Scholar
- Chung RS, Penkowa M, Dittmann J, King CE, Bartlett C, Asmussen JW, Hidalgo J, Carrasco J, Leung YKJ, Walker AK, Fung SJ, Dunlop SA, Fitzgerald M, Beazley LD, Chuah MI, Vickers JC, West AK (2008) Redefining the role of metallothionein within the injured brain: extracellular metallothioneins play an important role in the astrocyte-neuron response to injury. J Biol Chem 283(22):15349–15358CrossRefPubMedGoogle Scholar
- Cohen G (1985) The Fenton reaction. In: Greenwald RA (ed) CRC Handbook of methods for oxygen radical research, CRC Press, Inc., Boca Raton, FL, pp. 55–64Google Scholar
- Deplanque D, Patrice M, Puisieux F, Pu Q, Robin E, Martin A, Bastide M, Leys D, Lhermitte M, Dupuis B (2000) Increase in endogenous brain superoxide dismutase as a potential mechanism of lipopolysaccharide-induced brain ischemic tolerance. J Cereb Blood Flow Metab 20(8):1190–1196PubMedGoogle Scholar
- Hinerfeld D, Traini MD, Weinberger RP, Cochran B, Doctrow SR, Harry J, Melov S (2004) Endogenous mitochondrial oxidative stress: neurodegeneration, proteomic analysis, specific respiratory chain defects, and efficacious antioxidant therapy in superoxide dismutase 2 null mice. J Neurochem 88(3):657–667CrossRefPubMedGoogle Scholar
- Keller JN, Kindy MS, Holtsberg FW, St. Clair DK, Yen H, Germeyer A, Steiner SM, Bruce-Keller AJ, Hutchins JB, Mattson MP (1998) Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. J Neurosci 18(2):687–697PubMedGoogle Scholar