Abstract
Abstract 39: Targeting Neutrophil-specific Integrin Alpha9 In Obesity-induced Hyperglycemia Mice Improves Stroke Outcome
Stroke (1970), Vol.54(S_1), p.A39
02/01/2023
DOI: 10.1161/str.54.suppl_1.39
Abstract
Byline: Rakeshkumar Patel, Univ of Iowa, IOWA city, IA; Nirav Dhanesha, Univ of Iowa, Iowa city, IA; Brijesh Sutariya, Univ of Iowa, Iowa city, IA; Madankumar Ghatge, Univ of Iowa, Iowa City, IA; Mariia Kumskova, Univ of Iowa, Iowa City, IA; Enrique C Leira, Univ of Iowa, Iowa City, IA; Anil K Chauhan, Univ of Iowa, Iowa City, IA Background: Obesity-induced hyperglycemia is one of the significant risk factors for stroke. Integrin ð9ð1 is highly expressed on activated neutrophils and stabilizes adhesion to the endothelium via ligands, including tenascin C. While myeloid deletion of ð9 reduces susceptibility to ischemic stroke, it is unclear whether this is mediated by neutrophil-derived ð9. Purpose: To determine the role of neutrophil-specific ð9 in stroke outcome in mice with obesity-induced hyperglycemia. Methods: ð9Neu-KO (ð9fl/flMRP8Cre+) and littermate control ð9WT (ð9fl/flMRP8 Cre-) mice were fed a 60% high fat diet for 20 weeks. Functional outcomes were evaluated up to 28 days after stroke in mice of both sexes using a transient (30 min) middle cerebral artery ischemia. Infarct volume (MRI) and post-reperfusion thrombo-inflammation (thrombi, fibrin, neutrophil, p-NFð¦B, NETosis, TNFð, and IL1ð levels) were measured post 6 or 48 h of reperfusion. Functional outcomes (mNSS, rotarod, corner, and wire-hanging test) were measured at week 1, 2, 3, and 4. Results: Stroke upregulated neutrophil ð9 expression in obese mice (P<.05 vs. lean mice). Genetic ablation of neutrophil-specific ð9 improved functional outcomes up to 4 weeks that was concomitant with reduced infarct size, improved CBF, decreased post-reperfusion thrombo-inflammation, and reduced NETosis (P<.05 vs. ð9WT obese mice) irrespective of sex. Intravital microscopy revealed that obese ð9Neu-KO mice were less susceptible to experimental carotid thrombosis (P<.05 vs. ð9WT obese mice). Infusion of tenascin C increased stroke severity in both ð9Neu-KO and ð9WT compared to vehicle, suggesting that neutrophil-specific ð9 does not exacerbate stroke via tenascin C. Obese WT mice infused with a blocking anti-integrin ð9 IgG exhibited improved functional outcomes up to 4 weeks (P<.05 vs. control IgG). Functional outcomes after stroke were comparable in ð9Neu-KO mice infused with anti-integrin ð9 IgG or control IgG, suggesting no off-target effects of the antibody. Conclusion: Both genetic ablation of neutrophil-specific ð9 and pharmacological inhibition improve long-term functional outcomes after stroke in mice with obesity-induced hyperglycemia, most likely by limiting thrombo-inflammation and NETosis.
Details
- Title: Subtitle
- Abstract 39: Targeting Neutrophil-specific Integrin Alpha9 In Obesity-induced Hyperglycemia Mice Improves Stroke Outcome
- Creators
- Rakeshkumar Patel - University of IowaNirav Dhanesha - University of IowaBrijesh Sutariya - University of IowaMadankumar Ghatge - University of IowaMariia Kumskova - University of IowaEnrique C Leira - University of IowaAnil K Chauhan - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Stroke (1970), Vol.54(S_1), p.A39
- Publisher
- Lippincott Williams & Wilkins, WK Health
- DOI
- 10.1161/str.54.suppl_1.39
- ISSN
- 0039-2499
- eISSN
- 1524-4628
- Language
- English
- Date published
- 02/01/2023
- Description audience
- Academic
- Academic Unit
- Neurosurgery; Epidemiology; Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine; Neurology; Iowa Neuroscience Institute
- Record Identifier
- 9984367615102771
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