Please use this identifier to cite or link to this item: http://bura.brunel.ac.uk/handle/2438/19067
Title: Novel Role for the AnxA1-Fpr2/ALX Signaling Axis as a Key Regulator of Platelet Function to Promote Resolution of Inflammation
Authors: Senchenkova, EY
Ansari, J
Becker, F
Vital, SA
Al-Yafeai, Z
Sparkenbaugh, EM
Pawlinski, R
Stokes, KY
Carroll, JL
Dragoi, AM
Qin, CX
Ritchie, RH
Sun, H
Cuellar-Saenz, HH
Rubinstein, MR
Han, YW
Orr, AW
Perretti, M
Granger, DN
Gavins, FNE
Keywords: annexin A1;formyl peptide receptor;inflammation;integrins;stroke;thrombosis
Issue Date: 3-Jul-2019
Publisher: American Heart Association
Citation: Circulation, 2019, 140 (4), pp. 319 - 335
Abstract: 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 B2 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 αIIbβ3 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 (αIIbβ3) 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.
URI: http://bura.brunel.ac.uk/handle/2438/19067
DOI: http://dx.doi.org/10.1161/CIRCULATIONAHA.118.039345
ISSN: http://dx.doi.org/10.1161/CIRCULATIONAHA.118.039345
1524-4539
Appears in Collections:Dept of Life Sciences Research Papers

Files in This Item:
File Description SizeFormat 
FullText.pdf2.43 MBAdobe PDFView/Open


Items in BURA are protected by copyright, with all rights reserved, unless otherwise indicated.