QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, December 13, 2006, 26(50):12904-12913; doi:10.1523/JNEUROSCI.2531-06.2006

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Liu, Y. Articles by Fassbender, K. Search for Related Content PubMed PubMed Citation Articles by Liu, Y. Articles by Fassbender, K.

 Previous Article  |  Next Article 

Neurobiology of Disease
Suppression of Microglial Inflammatory Activity by Myelin Phagocytosis: Role of p47-PHOX-Mediated Generation of Reactive Oxygen Species

Yang Liu,^1 * Wenlin Hao,^1,3 * Maryse Letiembre,¹ Silke Walter,¹ Miroslav Kulanga,¹ Harald Neumann,^2,3 and Klaus Fassbender¹

¹Department of Neurology, University of the Saarland, 66421 Homburg/Saar, Germany, ²Neural Regeneration Unit, Institute of Reconstructive Neurobiology, University of Bonn Life and Brain Center and Hertie Foundation, 53127 Bonn, Germany, and ³Neuroimmunology Unit, European Neuroscience Institute Göttingen, University of Göttingen, 37073 Göttingen, Germany

Correspondence should be addressed to Yang Liu or Klaus Fassbender, Department of Neurology, University of the Saarland, Kirrberger Straße, 66421 Homburg/Saar, Germany. Email: a.liu{at}mx.uni-saarland.de; Email: klaus.fassbender{at}uniklinikum-saarland.de

Multiple sclerosis (MS) is pathologically characterized by inflammatory demyelination and neuronal injury. Although phagocytosis of myelin debris by microglia and macrophages in acute MS lesions is well documented, its pathophysiological significance is unclear. Using real-time quantitative PCR, flow cytometry, ELISA, and reactive oxygen species (ROS) measurement assays, we demonstrated that phagocytosis of myelin modulates activation of microglial cells prestimulated by interferon- (IFN-) or a combination of IFN- and lipopolysaccharide with a biphasic temporal pattern, i.e., enhanced production of proinflammatory mediators during the first phase (6 h), followed by suppression during the second (6–24 h) phase. In this second phase, myelin phagocytosis leads to an enhanced release of prostaglandin E2 and ROS in microglia, whereas the production of anti-inflammatory cytokines (particularly interleukin-10) remains unchanged. Suppression of inflammatory microglial activation by myelin phagocytosis was reversed by treatment with superoxide dismutase and catalase, by inhibition of the NADPH–oxidase complex, or by specific knockdown of the NADPH–oxidase-required adaptor p47–phagocyte oxidase (PHOX). Furthermore, we observed that myelin phagocytosis destabilized tumor necrosis factor- and interferon-induced protein-10 mRNA through an adenine–uridine-rich elements-involved mechanism, which was reversed by blocking the function of NADPH–oxidase complex. We conclude that phagocytosis of myelin suppresses microglial inflammatory activities via enhancement of p47-PHOX-mediated ROS generation. These results suggest that intervention in ROS generation could represent a novel therapeutic strategy to reduce neuroinflammation in MS.

Key words: multiple sclerosis; inflammation; myelin; phagocytosis; reactive oxygen species; Ncf1

---

Received June 15, 2006; revised Oct. 18, 2006; accepted Oct. 21, 2006.

Correspondence should be addressed to Yang Liu or Klaus Fassbender, Department of Neurology, University of the Saarland, Kirrberger Straße, 66421 Homburg/Saar, Germany. Email: a.liu{at}mx.uni-saarland.de; Email: klaus.fassbender{at}uniklinikum-saarland.de

This article has been cited by other articles:

				Y. Liu, W. Hao, A. Dawson, S. Liu, and K. Fassbender Expression of Amyotrophic Lateral Sclerosis-linked SOD1 Mutant Increases the Neurotoxic Potential of Microglia via TLR2 J. Biol. Chem., February 6, 2009; 284(6): 3691 - 3699. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help