title: Endogenous transforming growth factor beta 1 suppresses inflammation and promotes survival in adult CNS.
abstract: Transforming growth factor beta1 (TGFbeta1) 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 TGFbeta1 and the effects of TGFbeta1 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 TGFbeta1-deficient mice, this study was performed on a T- and B-cell-deficient RAG2-/- background. Compared with wild-type siblings, homozygous deletion of TGFbeta1 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 [alphaXbeta2, 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 TGFbeta1 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), alpha6beta1, and alphaMbeta2] and reduced proliferation. In line with axonal and glial findings in the otherwise uninjured CNS, absence of endogenous TGFbeta1 also caused an approximately 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.
authors.affiliation: Perinatal Brain Repair Group, Department of Obstetrics and Gynaecology, University College London, London WC1E 6HX, United Kingdom.
authors.forename: Milan
authors.initials: M
authors.lastname: Makwana
authors.forename: Leonard L
authors.initials: LL
authors.lastname: Jones
authors.forename: Dan
authors.initials: D
authors.lastname: Cuthill
authors.forename: Heike
authors.initials: H
authors.lastname: Heuer
authors.forename: Marion
authors.initials: M
authors.lastname: Bohatschek
authors.forename: Mariya
authors.initials: M
authors.lastname: Hristova
authors.forename: Sönke
authors.initials: S
authors.lastname: Friedrichsen
authors.forename: Ilona
authors.initials: I
authors.lastname: Ormsby
authors.forename: Dietmute
authors.initials: D
authors.lastname: Bueringer
authors.forename: Andrea
authors.initials: A
authors.lastname: Koppius
authors.forename: Karl
authors.initials: K
authors.lastname: Bauer
authors.forename: Thomas
authors.initials: T
authors.lastname: Doetschman
authors.forename: Gennadij
authors.initials: G
authors.lastname: Raivich
mesh_terms: D000367:Age Factors; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002490:Central Nervous System / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: D018836:Inflammation Mediators; D053773:Transforming Growth Factor beta1