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

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, October 17, 2007, 27(42):11201-11213; doi:10.1523/JNEUROSCI.2255-07.2007

This Article Full Text Full Text (PDF) 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 Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Makwana, M. Articles by Raivich, G. Search for Related Content PubMed PubMed Citation Articles by Makwana, M. Articles by Raivich, G.

 Previous Article  |  Next Article 

Neurobiology of Disease
Endogenous Transforming Growth Factor ß1 Suppresses Inflammation and Promotes Survival in Adult CNS

Milan Makwana,^1 * Leonard L. Jones,^2 * Dan Cuthill,^1 * Heike Heuer,^3,4 Marion Bohatschek,¹ Mariya Hristova,¹ Sönke Friedrichsen,³ Ilona Ormsby,⁵ Dietmute Bueringer,² Andrea Koppius,² Karl Bauer,³ Thomas Doetschman,⁵ and Gennadij Raivich^1,2

¹Perinatal Brain Repair Group, Department of Obstetrics and Gynaecology and Department of Anatomy, University College London, London WC1E 6HX, United Kingdom, ²Department of Neuromorphology, Max-Planck Institute of Neurobiology, D-82152 Martinsried, Germany, ³Max-Planck Institute of Experimental Endocrinology, D-30625 Hannover, Germany, ⁴Neuroendocrinology Group, Leibniz Institute for Age Research-Fritz-Lipmann-Institute, D-07745 Jena, Germany, and ⁵Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267

Correspondence should be addressed to Dr. Gennadij Raivich, Perinatal Brain Repair Group, Department of Obstetrics and Gynaecology and Department of Anatomy, University College London, Chenies Mews 86–96, London WC1E 6HX, UK. Email: g.raivich{at}ucl.ac.uk

Transforming growth factor ß1 (TGFß1) is a pleiotropic cytokine with potent neurotrophic and immunosuppressive properties that is upregulated after injury, but also expressed in the normal nervous system. In the current study, we examined the regulation of TGFß1 and the effects of TGFß1 deletion on cellular response in the uninjured adult brain and in the injured and regenerating facial motor nucleus. To avoid lethal autoimmune inflammation within 3 weeks after birth in TGFß1-deficient mice, this study was performed on a T- and B-cell-deficient RAG2–/– background. Compared with wild-type siblings, homozygous deletion of TGFß1 resulted in an extensive inflammatory response in otherwise uninjured brain parenchyma. Astrocytes increased in GFAP and CD44 immunoreactivity; microglia showed proliferative activity, expression of phagocytosis-associated markers [Xß2, B7.2, and MHC1 (major histocompatibility complex type 1)], and reduced branching. Ultrastructural analysis revealed focal blockade of axonal transport, perinodal damming of axonal organelles, focal demyelination, and myelin debris in granule-rich, phagocytic microglia. After facial axotomy, absence of TGFß1 led to a fourfold increase in neuronal cell death (52 vs 13%), decreased central axonal sprouting, and significant delay in functional recovery. It also interfered with the microglial response, resulting in a diminished expression of early activation markers [ICAM1 (intercellular adhesion molecule 1), 6ß1, and Mß2] and reduced proliferation. In line with axonal and glial findings in the otherwise uninjured CNS, absence of endogenous TGFß1 also caused an 10% reduction in the number of normal motoneurons, pointing to an ongoing and potent trophic role of this anti-inflammatory cytokine in the normal as well as in the injured brain.

Key words: microglia; astrocyte; inflammation; cell death; axonal dystrophy; demyelination

---

Received May 17, 2007; revised Aug. 28, 2007; accepted Aug. 28, 2007.

Correspondence should be addressed to Dr. Gennadij Raivich, Perinatal Brain Repair Group, Department of Obstetrics and Gynaecology and Department of Anatomy, University College London, Chenies Mews 86–96, London WC1E 6HX, UK. Email: g.raivich{at}ucl.ac.uk

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help