Journal article
Targeting Myeloid-Specific Integrin alpha 9 beta 1 Improves Short- and Long-Term Stroke Outcomes in Murine Models With Preexisting Comorbidities by Limiting Thrombosis and Inflammation
Circulation research, Vol.126(12), pp.1779-1794
06/05/2020
DOI: 10.1161/CIRCRESAHA.120.316659
PMCID: PMC7274887
PMID: 32195632
Abstract
Rationale: Currently, there is no effective intervention available that can reduce brain damage following reperfusion. Clinical studies suggest a positive correlation between the increased influx of neutrophils and severity of brain injury following reperfusion. Integrin alpha 9 beta 1 is highly expressed on activated neutrophils and contributes to stable adhesion, but its role in stroke outcome has not been demonstrated to date. Objective: We sought to determine the mechanistic role of myeloid-specific alpha 9 beta 1 in the progression of ischemic stroke in murine models with preexisting comorbidities. Methods and Results: We generated novel myeloid-specific alpha 9-deficient (alpha 9(-/-)) wild type (alpha 9(fl/fl)LysMCre(+/-)), hyperlipidemic (alpha 9(fl/fl)LysMCre(+/-)Apoe(-/-)), and aged (bone marrow chimeric) mice to evaluate stroke outcome. Susceptibility to ischemia/reperfusion injury was evaluated at 1, 7, and 28 days following reperfusion in 2 models of experimental stroke: filament and embolic. We found that peripheral neutrophils displayed elevated alpha 9 expression following stroke. Irrespective of sex, genetic deletion of alpha 9 in myeloid cells improved short- and long-term stroke outcomes in the wild type, hyperlipidemic, and aged mice. Improved stroke outcome and enhanced survival in myeloid-specific alpha 9(-/-)mice was because of marked decrease in cerebral thromboinflammatory response as evidenced by reduced fibrin, platelet thrombi, neutrophil, NETosis, and decreased phospho-NF-kappa B (nuclear factor-kappa B), TNF (tumor necrosis factor)-alpha, and IL (interleukin)-1 beta levels.alpha 9(-/-)mice were less susceptible to FeCl(3)injury-induced carotid artery thrombosis that was concomitant with improved regional cerebral blood flow following stroke as revealed by laser speckle imaging. Mechanistically, fibronectin containing extra domain A, a ligand for integrin alpha 9, partially contributed to alpha 9-mediated stroke exacerbation. Infusion of a specific anti-integrin alpha 9 inhibitor into hyperlipidemic mice following reperfusion significantly reduced infarct volume and improved short- and long-term functional outcomes up to 28 days. Conclusions: We provide genetic and pharmacological evidence for the first time that targeting myeloid-specific integrin alpha 9 beta 1 improves short- and long-term functional outcomes in stroke models with preexisting comorbidities by limiting cerebral thrombosis and inflammation.
Details
- Title: Subtitle
- Targeting Myeloid-Specific Integrin alpha 9 beta 1 Improves Short- and Long-Term Stroke Outcomes in Murine Models With Preexisting Comorbidities by Limiting Thrombosis and Inflammation
- Creators
- Nirav Dhanesha - University of IowaManish Jain - University of IowaAmit K. Tripathi - University of IowaPrakash Doddapattar - University of IowaMehul Chorawala - University of IowaGirish Bathla - University of IowaManasa K. Nayak - University of IowaMadankumar Ghatge - University of IowaSteven R. Lentz - University of IowaShigeyuki Kon - Fukuyama UniversityAnil K. Chauhane - Univ Iowa, Dept Internal Med, Div Hematol Oncol, Iowa City, IA 52242 USA
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.126(12), pp.1779-1794
- Publisher
- Lippincott Williams & Wilkins
- DOI
- 10.1161/CIRCRESAHA.120.316659
- PMID
- 32195632
- PMCID
- PMC7274887
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Number of pages
- 16
- Grant note
- American Society of Hematology 18EIA33900009 / American Heart Association R35HL139926; R01NS109910; U01NS113388 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 06/05/2020
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359784702771
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