Interactions between integrin α9β1 and VCAM-1 promote neutrophil hyperactivation and mediate poststroke DVT.

Autor:	Pandey N; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA., Kaur H; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA., Chorawala MR; Department of Pharmacology and Pharmacy Practice, L.M. College of Pharmacy, Ahmedabad, India., Anand SK; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA., Chandaluri L; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA., Butler ME; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA., Aishwarya R; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA., Gaddam SJ; Department of Hematology and Oncology and Feist Weiller Cancer Center, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA., Shen X; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA., Alfaidi M; Division of Cardiology, Department of Internal Medicine, Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA., Wang J; Bioinformatics and Modeling Core, Center for Applied Immunology and Pathological Processes, Department of Microbiology and Immunology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA., Zhang X; Bioinformatics and Modeling Core, Center for Applied Immunology and Pathological Processes, Department of Microbiology and Immunology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA., Beedupalli K; Department of Hematology and Oncology and Feist Weiller Cancer Center, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA., Bhuiyan MS; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA.; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA., Bhuiyan MAN; Department of Medicine, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA., Buchhanolla P; Department of Neurology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA., Rai P; Department of Neurology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA., Shah R; Department of Neurology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA., Chokhawala H; Department of Neurology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA., Jordan JD; Department of Neurology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA., Magdy T; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA., Orr AW; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA.; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA., Stokes KY; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA., Rom O; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA.; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA., Dhanesha N; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2024 May 14; Vol. 8 (9), pp. 2104-2117.
DOI:	10.1182/bloodadvances.2023012282
Abstrakt:	Abstract: Venous thromboembolic events are significant contributors to morbidity and mortality in patients with stroke. Neutrophils are among the first cells in the blood to respond to stroke and are known to promote deep vein thrombosis (DVT). Integrin α9 is a transmembrane glycoprotein highly expressed on neutrophils and stabilizes neutrophil adhesion to activated endothelium via vascular cell adhesion molecule 1 (VCAM-1). Nevertheless, the causative role of neutrophil integrin α9 in poststroke DVT remains unknown. Here, we found higher neutrophil integrin α9 and plasma VCAM-1 levels in humans and mice with stroke. Using mice with embolic stroke, we observed enhanced DVT severity in a novel model of poststroke DVT. Neutrophil-specific integrin α9-deficient mice (α9fl/flMrp8Cre+/-) exhibited a significant reduction in poststroke DVT severity along with decreased neutrophils and citrullinated histone H3 in thrombi. Unbiased transcriptomics indicated that α9/VCAM-1 interactions induced pathways related to neutrophil inflammation, exocytosis, NF-κB signaling, and chemotaxis. Mechanistic studies revealed that integrin α9/VCAM-1 interactions mediate neutrophil adhesion at the venous shear rate, promote neutrophil hyperactivation, increase phosphorylation of extracellular signal-regulated kinase, and induce endothelial cell apoptosis. Using pharmacogenomic profiling, virtual screening, and in vitro assays, we identified macitentan as a potent inhibitor of integrin α9/VCAM-1 interactions and neutrophil adhesion to activated endothelial cells. Macitentan reduced DVT severity in control mice with and without stroke, but not in α9fl/flMrp8Cre+/- mice, suggesting that macitentan improves DVT outcomes by inhibiting neutrophil integrin α9. Collectively, we uncovered a previously unrecognized and critical pathway involving the α9/VCAM-1 axis in neutrophil hyperactivation and DVT. (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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