title: Essential role of interleukin-6 in post-stroke angiogenesis.
abstract: Ambivalent effects of interleukin-6 on the pathogenesis of ischaemic stroke have been reported. However, to date, the long-term actions of interleukin-6 after stroke have not been investigated. Here, we subjected interleukin-6 knockout (IL-6(-/-)) and wild-type control mice to mild brain ischaemia by 30-min filamentous middle cerebral artery occlusion/reperfusion. While ischaemic tissue damage was comparable at early time points, IL-6(-/-) mice showed significantly increased chronic lesion volumes as well as worse long-term functional outcome. In particular, IL-6(-/-) mice displayed an impaired angiogenic response to brain ischaemia with reduced numbers of newly generated endothelial cells and decreased density of perfused microvessels along with lower absolute regional cerebral blood flow and reduced vessel responsivity in ischaemic striatum at 4 weeks. Similarly, the early genomic activation of angiogenesis-related gene networks was strongly reduced and the ischaemia-induced signal transducer and activator of transcription 3 activation observed in wild-type mice was almost absent in IL-6(-/-) mice. In addition, systemic neoangiogenesis was impaired in IL-6(-/-) mice. Transplantation of interleukin-6 competent bone marrow into IL-6(-/-) mice (IL-6(chi)) did not rescue interleukin-6 messenger RNA expression or the early transcriptional activation of angiogenesis after stroke. Accordingly, chronic stroke outcome in IL-6(chi) mice recapitulated the major effects of interleukin-6 deficiency on post-stroke regeneration with significantly enhanced lesion volumes and reduced vessel densities. Additional in vitro experiments yielded complementary evidence, which showed that after stroke resident brain cells serve as the major source of interleukin-6 in a self-amplifying network. Treatment of primary cortical neurons, mixed glial cultures or immortalized brain endothelia with interleukin 6-induced robust interleukin-6 messenger RNA transcription in each case, whereas oxygen-glucose deprivation did not. However, oxygen-glucose deprivation of organotypic brain slices resulted in strong upregulation of interleukin-6 messenger RNA along with increased transcription of key angiogenesis-associated genes. In conclusion, interleukin-6 produced locally by resident brain cells promotes post-stroke angiogenesis and thereby affords long-term histological and functional protection.
authors.affiliation: Department of Neurology, Charité– Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Gertz
authors.forename: Golo
authors.initials: G
authors.lastname: Kronenberg
authors.forename: Roland E
authors.initials: RE
authors.lastname: Kälin
authors.forename: Tina
authors.initials: T
authors.lastname: Baldinger
authors.forename: Christian
authors.initials: C
authors.lastname: Werner
authors.forename: Mustafa
authors.initials: M
authors.lastname: Balkaya
authors.forename: Gina D
authors.initials: GD
authors.lastname: Eom
authors.forename: Julian
authors.initials: J
authors.lastname: Hellmann-Regen
authors.forename: Jan
authors.initials: J
authors.lastname: Kröber
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Miller
authors.forename: Ute
authors.initials: U
authors.lastname: Lindauer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Laufs
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
authors.forename: Frank L
authors.initials: FL
authors.lastname: Heppner
authors.forename: Matthias
authors.initials: M
authors.lastname: Endres
mesh_terms: D000704:Analysis of Variance; D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods; D001921:Brain / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D042783:Endothelial Cells / Q000473:pathology; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D020233:Gait Disorders, Neurologic / Q000209:etiology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D005947:Glucose / Q000172:deficiency; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia / Q000150:complications; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D008840:Microfilament Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000378:metabolism; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D055420:Perfusion Imaging; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D045442:Rotarod Performance Test; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: C491049:Aif1 protein, mouse; D042501:Angiogenic Proteins; D002135:Calcium-Binding Proteins; D016207:Cytokines; D019332:Endothelin-1; C494200:Il6st protein, mouse; D015850:Interleukin-6; D008840:Microfilament Proteins; D050796:STAT3 Transcription Factor; D013778:Tetrazolium Salts; D013844:Thiazoles; D050822:Cytokine Receptor gp130; D049452:Green Fluorescent Proteins; D020813:Receptor, trkB; C022616:thiazolyl blue; D005947:Glucose