Novel Role for the AnxA1-Fpr2/ALX Signaling Axis as a Key Regulator of Platelet Function to Promote Resolution of Inflammation.

Autor: Senchenkova EY; Departments of Molecular and Cellular Physiology (E.Y.S., J.A., S.A.V., K.Y.S., D.N.G., F.N.E.G.)., Ansari J; Departments of Molecular and Cellular Physiology (E.Y.S., J.A., S.A.V., K.Y.S., D.N.G., F.N.E.G.)., Becker F; Department for General, Visceral, and Transplant Surgery, University Hospital Muenster, Germany (F.B., H.S.)., Vital SA; Departments of Molecular and Cellular Physiology (E.Y.S., J.A., S.A.V., K.Y.S., D.N.G., F.N.E.G.)., Al-Yafeai Z; Pathology and Translational Pathobiology (Z.A.-Y., A.W.O.)., Sparkenbaugh EM; Department of Medicine, University North Carolina Chapel Hill (E.M.S., R.P.)., Pawlinski R; Department of Medicine, University North Carolina Chapel Hill (E.M.S., R.P.)., Stokes KY; Departments of Molecular and Cellular Physiology (E.Y.S., J.A., S.A.V., K.Y.S., D.N.G., F.N.E.G.)., Carroll JL; INLET (J.L.C., A.-M.D.).; Feist-Weiller Cancer Center (J.L.C., A.-M.D.), Louisiana State University Health Sciences Center-Shreveport., Dragoi AM; INLET (J.L.C., A.-M.D.).; Feist-Weiller Cancer Center (J.L.C., A.-M.D.), Louisiana State University Health Sciences Center-Shreveport., Qin CX; Heart Failure Pharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (C.X.Q., R.H.R.)., Ritchie RH; Heart Failure Pharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (C.X.Q., R.H.R.)., Sun H; Neurosurgery (H.S., H.H.C.-Z.).; Department for General, Visceral, and Transplant Surgery, University Hospital Muenster, Germany (F.B., H.S.)., Cuellar-Saenz HH; Neurosurgery (H.S., H.H.C.-Z.)., Rubinstein MR; Division of Periodontics, College of Dental Medicine (M.R.R., Y.W.H.), Columbia University, New York., Han YW; Division of Periodontics, College of Dental Medicine (M.R.R., Y.W.H.), Columbia University, New York.; Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons (Y.W.H.), Columbia University, New York., Orr AW; Pathology and Translational Pathobiology (Z.A.-Y., A.W.O.).; Cellular Biology and Anatomy (A.W.O.)., Perretti M; William Harvey Research Institute, Queen Mary University of London, UK (M.P.)., Granger DN; Departments of Molecular and Cellular Physiology (E.Y.S., J.A., S.A.V., K.Y.S., D.N.G., F.N.E.G.)., Gavins FNE; Departments of Molecular and Cellular Physiology (E.Y.S., J.A., S.A.V., K.Y.S., D.N.G., F.N.E.G.).; Department of Life Sciences, Brunel University London, Uxbridge, Middlesex, UK (F.N.E.G.).
Jazyk: angličtina
Zdroj: Circulation [Circulation] 2019 Jul 23; Vol. 140 (4), pp. 319-335. Date of Electronic Publication: 2019 Jun 03.
DOI: 10.1161/CIRCULATIONAHA.118.039345
Abstrakt: Background: Ischemia reperfusion injury (I/RI) is a common complication of cardiovascular diseases. Resolution of detrimental I/RI-generated prothrombotic and proinflammatory responses is essential to restore homeostasis. Platelets play a crucial part in the integration of thrombosis and inflammation. Their role as participants in the resolution of thromboinflammation is underappreciated; therefore we used pharmacological and genetic approaches, coupled with murine and clinical samples, to uncover key concepts underlying this role.
Methods: Middle cerebral artery occlusion with reperfusion was performed in wild-type or annexin A1 (AnxA1) knockout (AnxA1 -/- ) mice. Fluorescence intravital microscopy was used to visualize cellular trafficking and to monitor light/dye-induced thrombosis. The mice were treated with vehicle, AnxA1 (3.3 mg/kg), WRW4 (1.8 mg/kg), or all 3, and the effect of AnxA1 was determined in vivo and in vitro.
Results: Intravital microscopy revealed heightened platelet adherence and aggregate formation post I/RI, which were further exacerbated in AnxA1 -/- mice. AnxA1 administration regulated platelet function directly (eg, via reducing thromboxane B 2 and modulating phosphatidylserine expression) to promote cerebral protection post-I/RI and act as an effective preventative strategy for stroke by reducing platelet activation, aggregate formation, and cerebral thrombosis, a prerequisite for ischemic stroke. To translate these findings into a clinical setting, we show that AnxA1 plasma levels are reduced in human and murine stroke and that AnxA1 is able to act on human platelets, suppressing classic thrombin-induced inside-out signaling events (eg, Akt activation, intracellular calcium release, and Ras-associated protein 1 [Rap1] expression) to decrease α IIb β 3 activation without altering its surface expression. AnxA1 also selectively modifies cell surface determinants (eg, phosphatidylserine) to promote platelet phagocytosis by neutrophils, thereby driving active resolution. (n=5-13 mice/group or 7-10 humans/group.) Conclusions: AnxA1 affords protection by altering the platelet phenotype in cerebral I/RI from propathogenic to regulatory and reducing the propensity for platelets to aggregate and cause thrombosis by affecting integrin (α IIb β 3 ) activation, a previously unknown phenomenon. Thus, our data reveal a novel multifaceted role for AnxA1 to act both as a therapeutic and a prophylactic drug via its ability to promote endogenous proresolving, antithromboinflammatory circuits in cerebral I/RI. Collectively, these results further advance our knowledge and understanding in the field of platelet and resolution biology.
Databáze: MEDLINE
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