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Eosinophil-platelet interactions promote atherosclerosis and stabilize thrombosis by eosinophil extracellular traps

Charlotte Marx, Julia Novotny, Danby Salbeck, Katie R. Zellner, Leo Nicolai, Kami Pekayvaz, Badr Kilani, Sven Stockhausen, Niklas Bürgener, Danny Kupka, Thomas J. Stocker, Ludwig T. Weckbach, Joachim Pircher, Markus Moser, Michael Joner, Walter Desmet, Tom Adriaenssens, Franz-Josef Neumann, Anthony H. Gershlick, Jurrien M. ten Berg, Michael Lorenz and Konstantin Stark

Key Points

  • Eosinophils promote atherosclerotic plaque formation and thrombosis

  • Eosinophils form extracellular traps in human and murine thrombi triggered by platelets, which enhance thrombus stability through MBP

Abstract

Clinical observations implicate a role of eosinophils in cardiovascular diseases, because markers of eosinophils activation are elevated in atherosclerosis and thrombosis. However, their contribution to atherosclerotic plaque formation and arterial thrombosis remains unclear. In these settings, we investigated how eosinophils are recruited and activated through an interplay with platelets. Here, we provide evidence for a central importance of eosinophil-platelet interactions in atherosclerosis and thrombosis. We show that eosinophils support atherosclerotic plaque formation involving enhanced von Willebrand factor exposure on endothelial cell and augmented platelet adhesion. During arterial thrombosis, eosinophils are quickly recruited in an integrin-dependent manner and engage in interactions with platelets leading to eosinophil activation as we show by intravital calcium imaging. These direct interactions induce the formation of eosinophil extracellular traps (EETs), which are present in human thrombi and constitute a substantial part of extracellular traps in murine thrombi. EETs are decorated with the granule protein major basic protein, which causes platelet activation by eosinophils. Consequently, targeting of EETs diminished thrombus formation in vivo identifying this approach as a novel antithrombotic concept. Finally, in our clinical analysis of coronary artery thrombi we identified female patients with stent thrombosis as the population that might derive the greatest benefit from an eosinophil inhibiting strategy. In summary, eosinophils contribute to atherosclerotic plaque formation and thrombosis through an interplay with platelets, resulting in mutual activation. Therefore, eosinophils are a promising new target in the prevention and therapy of atherosclerosis and thrombosis.

  • Submitted March 5, 2019.
  • Revision received August 28, 2019.
  • Accepted August 13, 2019.