期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 42, 期 10, 页码 1961-1974出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/0271678X221107871
关键词
Astrocytes; blood protein; inflammation; ischemia; sex dimorphism
资金
- NIH [NS102745]
Blood vitronectin (VTN) leaking into the brain after stroke exacerbates tissue loss by increasing IL-6 expression in female mice. Inhibiting focal adhesion kinase (FAK) reduces brain injury size, inflammation, and motor dysfunction in female, but not male, mice. Selective gene deletion of FAK in astrocytes reduces IL-6 expression and mitigates infarct size and inflammation. VTN signaling can be targeted to mitigate harmful inflammation in female stroke patients.
We found that blood vitronectin (VTN) leaks into the brain and exacerbates tissue loss after stroke by increasing pro-inflammatory IL-6 expression in female, but not male, mice. VTN signals through integrins and downstream focal adhesion kinase (FAK). Here, a two day systemic treatment with a small molecule FAK inhibitor starting 6 h after middle cerebral artery occlusion reduced ipsilateral brain injury size by similar to 40-45% at 7 and 14 d, as well as inflammation and motor dysfunction in wild-type female, but not male, mice. FAK inhibition also reduced IL-6 expression in the injured female striatum at 24 h by 62%. Inducible selective gene deletion of FAK in astrocytes also reduced acute IL-6 expression by 72% only in females, and mitigated infarct size by similar to 80% and inflammation at 14 d after stroke. Lastly, VTN-/- females had better outcomes, but FAK inhibitor treatment had no additional protective or anti-inflammatory effects. Altogether, this suggests that VTN is detrimental in females primarily through FAK and that FAK inhibition provides neuroprotection (cerebroprotection) by reducing VTN-induced IL-6 expression in astrocytes. Thus, VTN signaling can be targeted to mitigate harmful inflammation with relevance to treatments for women with ischemic stroke, who often have worse outcomes than men.
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