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

• Autores: Senchenkova, Elena Y.; Ansari, Junaid; Becker, Felix; Vital, Shantel A.; Al-Yafeai, Zaki; Sparkenbaugh, Erica M.; Pawlinski, Rafal; Stokes, Karen Y.; Carroll, Jennifer L.; Dragoi, Ana-Maria; Qin, Cheng Xue; Ritchie, Rebecca H.; Sun, Hai; Cuellar-Saenz, Hugo H.; Rubinstein Guichon, Mara Roxana; Han, Yiping W.; Orr, A. Wayne; Perretti, Mauro; Granger, D. Neil; Gavins, Felicity N.E.
• Año de publicación: 2019
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: ANNEXIN A1; FORMYL PEPTIDE RECEPTOR; INFLAMMATION; INTEGRINS; STROKE; THROMBOSIS
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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 IIbβ3 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 (IIbβ3) 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.
Fil: Senchenkova, Elena Y.. State University of Louisiana; Estados Unidos
Fil: Ansari, Junaid. State University of Louisiana; Estados Unidos
Fil: Becker, Felix. University Hospital Muenster; Alemania
Fil: Vital, Shantel A.. State University of Louisiana; Estados Unidos
Fil: Al-Yafeai, Zaki. State University of Louisiana; Estados Unidos
Fil: Sparkenbaugh, Erica M.. University North Carolina Chapel Hill; Estados Unidos
Fil: Pawlinski, Rafal. University North Carolina Chapel Hill; Estados Unidos
Fil: Stokes, Karen Y.. State University of Louisiana; Estados Unidos
Fil: Carroll, Jennifer L.. State University of Louisiana; Estados Unidos
Fil: Dragoi, Ana-Maria. State University of Louisiana; Estados Unidos
Fil: Qin, Cheng Xue. Baker Heart And Diabetes Institute; Australia
Fil: Ritchie, Rebecca H.. Baker Heart And Diabetes Institute; Australia
Fil: Sun, Hai. University Hospital Muenster; Alemania
Fil: Cuellar-Saenz, Hugo H.. State University of Louisiana; Estados Unidos
Fil: Rubinstein Guichon, Mara Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina. Columbia University; Estados Unidos
Fil: Han, Yiping W.. Columbia University; Estados Unidos
Fil: Orr, A. Wayne. University Hospital Muenster; Alemania
Fil: Perretti, Mauro. Queen Mary University Of London; Reino Unido
Fil: Granger, D. Neil. State University of Louisiana; Estados Unidos
Fil: Gavins, Felicity N.E.. State University of Louisiana; Estados Unidos