Page 209 - Haematologica - Vol. 105 n. 6 - June 2020

Platelet Biology & its Disorders
Coactosin-like 1 integrates signaling critical for shear-dependent thrombus formation in mouse platelets
Inga Scheller,1,2 Simon Stritt,1,2,° Sarah Beck,1,2 Bing Peng,3 Irina Pleines,1,2 Katrin G. Heinze,2 Attila Braun,1,2 Oliver Otto,4 Robert Ahrends,3 Albert Sickmann,3 Markus Bender,1,2 and Bernhard Nieswandt1,2
1Institute of Experimental Biomedicine I, University Hospital, University of Würzburg, Würzburg; 2Rudolf Virchow Center, University of Würzburg, Würzburg; 3Leibniz-Institut für Analytische Wissenschaften - ISAS – e.V., Lipidomics, Dortmund and 4Center for Innovation Competence - Humoral Immune Reactions in Cardiovascular Diseases, Biomechanics, University of Greifswald, Greifswald, Germany.
°Current affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
ABSTRACT
Platelet aggregate formation is a multistep process involving receptor- mediated, as well as biomechanical, signaling cascades, which are highly dependent on actin dynamics. We have previously shown that actin depolymerizing factor (ADF)/n-cofilin and Twinfilin 2a, members of the ADF homology (ADF-H) protein family, have distinct roles in platelet formation and function. Coactosin-like 1 (Cotl1) is another ADF-H protein that binds actin and was also shown to enhance biosynthesis of pro-inflam- matory leukotrienes (LT) in granulocytes. Here, we generated mice lacking Cotl1 in the megakaryocyte lineage (Cotl1-/-) to investigate its role in platelet production and function. Absence of Cotl1 had no impact on platelet counts, platelet activation or cytoskeletal reorganization under static condi- tions in vitro. In contrast, Cotl1 deficiency markedly affected platelet aggre- gate formation on collagen and adhesion to immobilized von Willebrand factor at high shear rates in vitro, pointing to an impaired function of the platelet mechanoreceptor glycoprotein (GP) Ib. Furthermore, Cotl1-/- platelets exhibited increased deformability at high shear rates, indicating that the GPIb defect may be linked to altered biomechanical properties of the deficient cells. In addition, we found that Cotl1 deficiency markedly affected platelet LT biosynthesis. Strikingly, exogenous LT addition restored defective aggregate formation of Cotl1-/- platelets at high shear in vitro, indi- cating a critical role of platelet-derived LT in thrombus formation. In vivo, Cotl1 deficiency translated into prolonged tail bleeding times and protec- tion from occlusive arterial thrombus formation. Together, our results show that Cotl1 in platelets is an integrator of biomechanical and LT signaling in hemostasis and thrombosis.
Introduction
Platelets are small anucleate cells that are essential for hemostasis and mainte- nance of vascular integrity, but are also implicated in thrombosis resulting in ischemia and infarction under pathological conditions.1 The classic, simplified model of platelet-dependent arterial thrombus formation comprises sequential steps, involving platelet deceleration on the injured vessel wall via interaction of the platelet mechanoreceptor glycoprotein (GP) Ib with von Willebrand factor (vWF) immobilized on the injured vessel wall. This is followed by cellular activation via the collagen receptor GPVI and G protein-coupled receptors (GPCR) stimulated by soluble agonists such as ADP, thromboxane A2 (TxA2) or thrombin. The final com- mon pathway of these activatory events is the functional upregulation of integrins, which mediate firm platelet adhesion and aggregation.
Ferrata Storti Foundation
Haematologica 2020 Volume 105(6):1667-1676
Correspondence:
BERNHARD NIESWANDT
bernhard.nieswandt@virchow.uni-wuerzburg.de
Received: April 29, 2019. Accepted: September 26, 2019. Pre-published: October 3, 2019.
doi:10.3324/haematol.2019.225516
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/6/1667
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