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TGF? signaling in the brain increases with aging and signals to astrocytes and innate immune cells in the weeks after stroke.

ABSTRACT: TGF? is both neuroprotective and a key immune system modulator and is likely to be an important target for future stroke therapy. The precise function of increased TGF-?1 after stroke is unknown and its pleiotropic nature means that it may convey a neuroprotective signal, orchestrate glial scarring or function as an important immune system regulator. We therefore investigated the time course and cell-specificity of TGF? signaling after stroke, and whether its signaling pattern is altered by gender and aging.We performed distal middle cerebral artery occlusion strokes on 5 and 18 month old TGF? reporter mice to get a readout of TGF? responses after stroke in real time. To determine which cell type is the source of increased TGF? production after stroke, brain sections were stained with an anti-TGF? antibody, colocalized with markers for reactive astrocytes, neurons, and activated microglia. To determine which cells are responding to TGF? after stroke, brain sections were double-labelled with anti-pSmad2, a marker of TGF? signaling, and markers of neurons, oligodendrocytes, endothelial cells, astrocytes and microglia.TGF? signaling increased 2 fold after stroke, beginning on day 1 and peaking on day 7. This pattern of increase was preserved in old animals and absolute TGF? signaling in the brain increased with age. Activated microglia and macrophages were the predominant source of increased TGF? after stroke and astrocytes and activated microglia and macrophages demonstrated dramatic upregulation of TGF? signaling after stroke. TGF? signaling in neurons and oligodendrocytes did not undergo marked changes.We found that TGF? signaling increases with age and that astrocytes and activated microglia and macrophages are the main cell types that undergo increased TGF? signaling in response to post-stroke increases in TGF?. Therefore increased TGF? after stroke likely regulates glial scar formation and the immune response to stroke.


PROVIDER: S-EPMC2958905 | BioStudies | 2010-01-01T00:00:00Z

REPOSITORIES: biostudies

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