Endogenous transforming growth factor β1 suppresses inflammation and promotes survival in adult CNS

Milan Makwana, Leonard L. Jones, Dan Cuthill, Heike Heuer, Marion Bohatschek, Mariya Hristova, Sönke Friedrichsen, Ilona Ormsby, Dietmute Bueringer, Andrea Koppius, Karl Bauer, Thomas Doetschman, Gennadij Raivich

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

Transforming growth factor β1 (TGFβ1) 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 TGFβ1 and the effects of TGFβ1 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 TGFβ1-deficient mice, this study was performed on a T- and B-cell-deficient RAG2-/- background. Compared with wild-type siblings, homozygous deletion of TGFβ1 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 [αXβ2, 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 TGFβ1 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), α6β1, and αMβ2] and reduced proliferation. In line with axonal and glial findings in the otherwise uninjured CNS, absence of endogenous TGFβ1 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.

Original languageEnglish (US)
Pages (from-to)11201-11213
Number of pages13
JournalJournal of Neuroscience
Volume27
Issue number42
DOIs
StatePublished - Oct 17 2007
Externally publishedYes

    Fingerprint

Keywords

  • Astrocyte
  • Axonal dystrophy
  • Cell death
  • Demyelination
  • Inflammation
  • Microglia

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Makwana, M., Jones, L. L., Cuthill, D., Heuer, H., Bohatschek, M., Hristova, M., Friedrichsen, S., Ormsby, I., Bueringer, D., Koppius, A., Bauer, K., Doetschman, T., & Raivich, G. (2007). Endogenous transforming growth factor β1 suppresses inflammation and promotes survival in adult CNS. Journal of Neuroscience, 27(42), 11201-11213. https://doi.org/10.1523/JNEUROSCI.2255-07.2007