{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:07:46Z","timestamp":1791216466260,"version":"4.1.0"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Obesity-induced hyperglycemia is a significant risk factor for stroke. Integrin \u03b19\u03b21 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 \u03b19 reduces susceptibility to ischemic stroke, it is unclear whether this is mediated by neutrophil-derived \u03b19. We determined the role of neutrophil-specific \u03b19 in stroke outcomes in a mice model with obesity-induced hyperglycemia.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              \u03b19\n              <jats:sup>Neu-KO<\/jats:sup>\n              (\u03b19\n              <jats:sup>fl\/fl<\/jats:sup>\n              MRP8Cre\n              <jats:sup>+<\/jats:sup>\n              ) and littermate control \u03b19\n              <jats:sup>WT<\/jats:sup>\n              (\u03b19\n              <jats:sup>fl\/fl<\/jats:sup>\n              MRP8Cre\n              <jats:sup>\u2212<\/jats:sup>\n              ) 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-NF\u03baB], TNF [tumor necrosis factor]-\u03b1, and IL [interleukin]-1\u03b2 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.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Stroke upregulated neutrophil \u03b19 expression more in obese mice (\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              &lt;0.05 versus lean mice). Irrespective of sex, deletion of neutrophil \u03b19 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) (\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              &lt;0.05 versus \u03b19\n              <jats:sup>WT<\/jats:sup>\n              obese mice). Obese \u03b19\n              <jats:sup>Neu-KO<\/jats:sup>\n              mice were less susceptible to thrombosis in FeCl\n              <jats:sub>3<\/jats:sub>\n              injury-induced carotid thrombosis model. Mechanistically, we found that \u03b19\/cellular fibronectin axis contributes to NETosis via ERK (extracellular signal-regulated kinase) and PAD4 (peptidyl arginine deiminase 4), and neutrophil \u03b19 worsens stroke outcomes via cellular fibronectin-EDA but not tenascin C. Obese wild-type mice infused with anti\u2013integrin \u03b19 exhibited improved functional outcomes up to 4 weeks (\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              &lt;0.05 versus vehicle).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>Genetic ablation of neutrophil-specific \u03b19 or pharmacological inhibition improves long-term functional outcomes after stroke in mice with obesity-induced hyperglycemia, most likely by limiting thrombo-inflammation.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/strokeaha.123.042714","type":"journal-article","created":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T09:00:23Z","timestamp":1689325223000},"page":"2409-2419","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":27,"title":["Targeting Neutrophil \u03b19 Improves Functional Outcomes After Stroke in Mice With Obesity-Induced Hyperglycemia"],"prefix":"10.1161","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9727-9738","authenticated-orcid":true,"given":"Rakesh B.","family":"Patel","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine (R.B.P., N.D., B.S., M.G., P.D., T.B., M.K., A.K.C.), University of Iowa, Iowa City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9268-4363","authenticated-orcid":true,"given":"Nirav","family":"Dhanesha","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine (R.B.P., N.D., B.S., M.G., P.D., T.B., M.K., A.K.C.), University of Iowa, Iowa City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8602-0966","authenticated-orcid":true,"given":"Brijesh","family":"Sutariya","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine (R.B.P., N.D., B.S., M.G., P.D., T.B., M.K., A.K.C.), University of Iowa, Iowa City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6606-0108","authenticated-orcid":true,"given":"Madankumar","family":"Ghatge","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine (R.B.P., N.D., B.S., M.G., P.D., T.B., M.K., A.K.C.), University of Iowa, Iowa City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4219-5240","authenticated-orcid":true,"given":"Prakash","family":"Doddapattar","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine (R.B.P., N.D., B.S., M.G., P.D., T.B., M.K., A.K.C.), University of Iowa, Iowa City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3878-5806","authenticated-orcid":true,"given":"Tarun","family":"Barbhuyan","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine (R.B.P., N.D., B.S., M.G., P.D., T.B., M.K., A.K.C.), University of Iowa, Iowa City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2477-3011","authenticated-orcid":true,"given":"Mariia","family":"Kumskova","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine (R.B.P., N.D., B.S., M.G., P.D., T.B., M.K., A.K.C.), University of Iowa, Iowa City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3695-2946","authenticated-orcid":true,"given":"Enrique C.","family":"Leira","sequence":"additional","affiliation":[{"name":"Departments of Neurology, 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