Platelet-derived integrin- and tetraspanin-enriched tethers exacerbate severe inflammation
Platelet integrin αIIbβ3 is essential for hemostasis, thrombosis, and inflammation. We found that ligation of αIIbβ3 by von Willebrand factor or fibrin under flow triggered its accumulation in plasma membrane extensions or "platelet-derived integrin- and tetraspanin-enriched tethers" (PITTs). PITTs remained anchored to leukocytes or endothelial cells, whereas the partially αIIbβ3-deficient platelet body detached. Although still responsive to stimuli, αIIbβ3-deficient platelets did not support thrombus formation. PITTs promoted leukocyte activation and vascular inflammation in mouse models of infection and endotoxemia, and αIIbβ3 blockade reduced immune-mediated tissue damage. In patients with sepsis, COVID-19, or severe infections, PITT formation and platelet αIIbβ3 loss correlated with disease severity and adverse outcomes. We propose that PITTs are proinflammatory structures that amplify immune responses while contributing to platelet dysfunction in thrombo-inflammatory disease.
Authors
- Mara Meub (ORCID: https://orcid.org/0000-0003-1358-4191)
- Carina Gross
- Stefano Navarro (ORCID: https://orcid.org/0000-0002-1112-8400)
- Charly Kusch (ORCID: https://orcid.org/0000-0002-9636-1972)
- Katrin G. Heinze (ORCID: https://orcid.org/0000-0003-2372-6800)
- Markus Bender (ORCID: https://orcid.org/0000-0002-2381-116X)
- Valeria Fumagalli (ORCID: https://orcid.org/0000-0003-2583-2498)
- Philipp Burkard (ORCID: https://orcid.org/0000-0001-9748-7967)
- Lukas Johannes Weiss (ORCID: https://orcid.org/0000-0002-7550-2115)
- Christian Hackenbroch (ORCID: https://orcid.org/0000-0003-4148-5035)
- W. Kastenmüller
- Oliver Andrés (ORCID: https://orcid.org/0000-0002-1510-4051)
- Joachim Schenk (ORCID: https://orcid.org/0000-0003-2100-7319)
- Ceylan Onursal (ORCID: https://orcid.org/0009-0002-2241-491X)
- Kristina Mott (ORCID: https://orcid.org/0000-0002-3223-6857)
- David Štegner
- Denise F. Johnson
- Matteo Iannacone (ORCID: https://orcid.org/0000-0002-9370-2671)
- Alan T. Nurden
- Klaus Ley (ORCID: https://orcid.org/0000-0003-1124-9592)
- Harald Schulze
- Paquita Nurden
- Sabrina Ivana Bonfiglio
- Markus Sauer
- Dennis Pfeiffer
- Bernhard Nieswandt
Institutions
- University of North Carolina at Chapel Hill (US)
- Vita-Salute San Raffaele University (IT)
- Augusta University (US)
- University of Würzburg (DE)
- Electrophysiology and Heart Modeling Institute (FR)
- Universitätsklinikum Würzburg (DE)
- Hôpital Xavier Arnozan (FR)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
Publication Details
- Journal
- Science
- Published
- 2026-01-22
- DOI
- https://doi.org/10.1126/science.adu2825
- Citations
- 2
- Primary Topic
- Platelet Disorders and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 35.41