Antagonistic Roles of Human Platelet Integrin αIIbβ3 and Chemokines in Regulating Neutrophil Activation and Fate on Arterial Thrombi Under Flow.

Autor: Schönichen C; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands (C.S., S.L.N.B., J.M.E.M.C., R.R.K., S.P.W., M.J.E.K., J.W.M.H., M.N.).; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany (C.S., K.J.)., Montague SJ; Institute of Cardiovascular Sciences, The Medical School, University of Birmingham, United Kingdom (S.J.M., S.P.W.)., Brouns SLN; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands (C.S., S.L.N.B., J.M.E.M.C., R.R.K., S.P.W., M.J.E.K., J.W.M.H., M.N.)., Burston JJ; Systems Immunity Research Institute, School of Medicine, Cardiff University, United Kingdom (J.J.B., V.B.O.)., Cosemans JMEM; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands (C.S., S.L.N.B., J.M.E.M.C., R.R.K., S.P.W., M.J.E.K., J.W.M.H., M.N.)., Jurk K; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany (C.S., K.J.).; Department of Anaesthesiology and Intensive Care, University Hospital Muenster, Germany (K.J., B.E.K.)., Kehrel BE; Department of Anaesthesiology and Intensive Care, University Hospital Muenster, Germany (K.J., B.E.K.)., Koenen RR; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands (C.S., S.L.N.B., J.M.E.M.C., R.R.K., S.P.W., M.J.E.K., J.W.M.H., M.N.)., Ní Áinle F; School of Medicine, University College Dublin, Ireland (F.N.Á.).; Department of Haematology, Mater Misericordiae University Hospital and Rotunda Hospital, Dublin, Ireland (F.N.Á.)., O'Donnell VB; Systems Immunity Research Institute, School of Medicine, Cardiff University, United Kingdom (J.J.B., V.B.O.)., Soehnlein O; Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Germany (O.S.).; Institute for Experimental Pathology, Center for Molecular Biology of Inflammation, Westfälische Wilhelms Universität, Münster, Germany (O.S.).; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (O.S.)., Watson SP; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands (C.S., S.L.N.B., J.M.E.M.C., R.R.K., S.P.W., M.J.E.K., J.W.M.H., M.N.).; Institute of Cardiovascular Sciences, The Medical School, University of Birmingham, United Kingdom (S.J.M., S.P.W.).; Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, the Midlands, United Kingdom (S.P.W.)., Kuijpers MJE; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands (C.S., S.L.N.B., J.M.E.M.C., R.R.K., S.P.W., M.J.E.K., J.W.M.H., M.N.).; Thrombosis Expertise Centre, Heart and Vascular Centre, Maastricht University Medical Centre, the Netherlands (M.J.E.K.)., Heemskerk JWM; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands (C.S., S.L.N.B., J.M.E.M.C., R.R.K., S.P.W., M.J.E.K., J.W.M.H., M.N.).; Synapse Research Institute, Maastricht, the Netherlands (J.W.M.H.)., Nagy M; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands (C.S., S.L.N.B., J.M.E.M.C., R.R.K., S.P.W., M.J.E.K., J.W.M.H., M.N.).
Jazyk: angličtina
Zdroj: Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2023 Sep; Vol. 43 (9), pp. 1700-1712. Date of Electronic Publication: 2023 Jul 06.
DOI: 10.1161/ATVBAHA.122.318767
Abstrakt: Background: Platelets and neutrophils are the first blood cells accumulating at sites of arterial thrombus formation, and both cell types contribute to the pathology of thrombotic events. We aimed to identify key interaction mechanisms between these cells using microfluidic approaches.
Methods: Whole-blood perfusion was performed over a collagen surface at arterial shear rate. Platelet and leukocyte (in majority neutrophil) activation were microscopically visualized using fluorescent markers. The contributions of platelet-adhesive receptors (integrin, P-selectin, CD40L) and chemokines were studied by using inhibitors or antibodies and using blood from patients with GT (Glanzmann thrombasthenia) lacking platelet-expressed αIIbβ3.
Results: We observed (1) an unknown role of activated platelet integrin αIIbß3 preventing leukocyte adhesion, which was overcome by short-term flow disturbance provoking massive adhesion; (2) that platelet-expressed CD40L controls the crawling pattern and thrombus fidelity of the cells on a thrombus; (3) that continued secretion of platelet substances promotes activation of identified neutrophils, as assessed by (fMLP [ N -formylmethionyl-leucyl-phenylalanine, a potent chemotactic agent and leukocyte activator] induced) [Ca 2+ ] i rises and antigen expression; (4) and that platelet-released chemokines activate the adhered cells in the order of CXCL7>CCL5>CXCL4. Furthermore, postsilencing of the platelets in a thrombus suppressed the leukocyte activation. However, the leukocytes on thrombi did no more than limitedly form neutrophil extracellular traps, unless stimulated with phorbol ester or lipopolysaccharide.
Conclusions: Together, these findings reveal a multifaceted regulation of adhesion and activation of neutrophils by platelets in a thrombus, with a balanced role of several platelet-adhesive receptors and a promoting role of platelet-released substances. This multivalent nature of neutrophil-thrombus interactions offers novel prospects for pharmacological intervention.
Competing Interests: Disclosures J.W.M. Heemskerk is scientific advisor of the Synapse Research Institute Maastricht. The other authors report no conflicts.
Databáze: MEDLINE
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