title: Microglia and macrophages are major sources of locally produced transforming growth factor-beta1 after transient middle cerebral artery occlusion in rats.
abstract: The potentially neurotrophic cytokine transforming growth factor-beta1 (TGF-beta1) is locally expressed following human stroke and experimental ischemic lesions, but the cellular source(s) and profile of induction have so far not been established in experimental focal cerebral ischemia. This study presents the time course and a cellular localization of TGF-beta1 mRNA, visualized by in situ hybridization combined with immunohistochemical staining for microglia, macrophages, or astrocytes, on brain sections from adult spontaneously hypertensive rats subjected to transient proximal occlusion of their middle cerebral artery. Six hours after ischemia, an early and transient neuronal and microglial expression of TGF-beta1 mRNA was observed in the extraischemic cingulate and frontal cortices. Both early and protracted expression of TGF-beta1 mRNA in the caudate-putamen and neocortical infarcts and in the caudate-putamen penumbra colocalized with OX42/ED1-immunoreactive microglia and macrophages, whereas TGF-beta1 mRNA in the neocortical penumbra colocalized with OX42/ED1-immunoreactive cells of a microglial morphology. No astrocytes were double-labeled. The number of TGF-beta1 mRNA-expressing microglia and macrophages increased strongly during the first week. Thereafter, TGF-beta1 mRNA became increasingly restricted to the neocortical penumbra (3 weeks), and after 3 months it was confined to activated microglia in the anterior commissure. Our data establish activated microglia and macrophages as the major source of TGF-beta1 mRNA following experimental focal cerebral ischemia. Consequently, TGF-beta1-mediated functions may be exerted by microglia both in the early degenerative phase, and later in combination with blood-borne macrophages, in the remodeling and healing phase after focal cerebral ischemia.
authors.affiliation: PharmaBiotec, Department of Anatomy and Cell Biology, Odense University, Denmark. elehrman@umaryland.edu
authors.forename: E
authors.initials: E
authors.lastname: Lehrmann
authors.forename: R
authors.initials: R
authors.lastname: Kiefer
authors.forename: T
authors.initials: T
authors.lastname: Christensen
authors.forename: K V
authors.initials: KV
authors.lastname: Toyka
authors.forename: J
authors.initials: J
authors.lastname: Zimmer
authors.forename: N H
authors.initials: NH
authors.lastname: Diemer
authors.forename: H P
authors.initials: HP
authors.lastname: Hartung
authors.forename: B
authors.initials: B
authors.lastname: Finsen
mesh_terms: D000818:Animals; D001157:Arterial Occlusive Diseases / Q000378:metabolism; D002536:Cerebral Arteries; D015870:Gene Expression; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D017628:Microglia / Q000378:metabolism*; D012333:RNA, Messenger; D051381:Rats; D011918:Rats, Inbred SHR; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D016212:Transforming Growth Factor beta