Journal article
Targeting Neutrophil α9 Improves Functional Outcomes After Stroke in Mice With Obesity-Induced Hyperglycemia
Stroke (1970), Vol.54(9), pp.2409-2419
09/2023
DOI: 10.1161/STROKEAHA.123.042714
PMCID: PMC10529694
PMID: 37449422
Abstract
Background: Obesity-induced hyperglycemia is a significant risk factor for stroke. Integrin α9β1 is expressed on neutrophils and stabilizes adhesion to the endothelium via ligands, including Fn-EDA (fibronectin containing extra domain A) and tenascin C. Although myeloid deletion of α9 reduces susceptibility to ischemic stroke, it is unclear whether this is mediated by neutrophil-derived α9. We determined the role of neutrophil-specific α9 in stroke outcomes in a mice model with obesity-induced hyperglycemia. Methods: α9 Neu-KO (α9 fl/fl MRP8Cre + ) and littermate control α9 WT (α9 fl/fl MRP8Cre − ) mice were fed on a 60% high-fat diet for 20 weeks to induce obesity-induced hyperglycemia. Functional outcomes were evaluated up to 28 days after stroke onset in mice of both sexes using a transient (30 minutes) middle cerebral artery ischemia. Infarct volume (magnetic resonance imaging) and postreperfusion thrombo-inflammation (thrombi, fibrin, neutrophil, phospho-nuclear factor kappa B [p-NFκB], TNF [tumor necrosis factor]-α, and IL [interleukin]-1β levels, markers of neutrophil extracellular traps) were measured post 6 or 48 hours of reperfusion. In addition, functional outcomes (modified Neurological Severity Score, rota-rod, corner, and wire-hanging test) were measured for up to 4 weeks. Results: Stroke upregulated neutrophil α9 expression more in obese mice ( P <0.05 versus lean mice). Irrespective of sex, deletion of neutrophil α9 improved functional outcomes up to 4 weeks, concomitant with reduced infarct, improved cerebral blood flow, decreased postreperfusion thrombo-inflammation, and neutrophil extracellular traps formation (NETosis) ( P <0.05 versus α9 WT obese mice). Obese α9 Neu-KO mice were less susceptible to thrombosis in FeCl 3 injury-induced carotid thrombosis model. Mechanistically, we found that α9/cellular fibronectin axis contributes to NETosis via ERK (extracellular signal-regulated kinase) and PAD4 (peptidyl arginine deiminase 4), and neutrophil α9 worsens stroke outcomes via cellular fibronectin-EDA but not tenascin C. Obese wild-type mice infused with anti–integrin α9 exhibited improved functional outcomes up to 4 weeks ( P <0.05 versus vehicle). Conclusions: Genetic ablation of neutrophil-specific α9 or pharmacological inhibition improves long-term functional outcomes after stroke in mice with obesity-induced hyperglycemia, most likely by limiting thrombo-inflammation.
Details
- Title: Subtitle
- Targeting Neutrophil α9 Improves Functional Outcomes After Stroke in Mice With Obesity-Induced Hyperglycemia
- Creators
- Rakesh B. Patel - University of IowaNirav Dhanesha - University of IowaBrijesh Sutariya - University of IowaMadankumar Ghatge - University of IowaPrakash Doddapattar - University of IowaTarun Barbhuyan - University of IowaMariia Kumskova - University of IowaEnrique C. Leira - University of IowaAnil K. Chauhan - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Stroke (1970), Vol.54(9), pp.2409-2419
- DOI
- 10.1161/STROKEAHA.123.042714
- PMID
- 37449422
- PMCID
- PMC10529694
- NLM abbreviation
- Stroke
- ISSN
- 0039-2499
- eISSN
- 1524-4628
- Language
- English
- Electronic publication date
- 07/14/2023
- Date published
- 09/2023
- Academic Unit
- Neurology; Hematology, Oncology, and Blood & Marrow Transplantation; Epidemiology; Iowa Neuroscience Institute; Neurosurgery; Internal Medicine
- Record Identifier
- 9984445076502771
Metrics
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