Platelet-derived serotonin drives age-related lung pathology in SARS-CoV-2 infection
Elderly individuals affected by COVID-19 are vulnerable to severe respiratory failure for reasons that have remained poorly defined. Here, we show that platelet-released serotonin drives lung pathology in a mouse model of age-associated disease severity after SARS-CoV-2 infection. In middle-aged mice and aged human healthy donors, platelet serotonin release upon activation was enhanced, and increased morbidity with respiratory dysfunction was associated with activated platelets aggregating and promoting fibrin deposition in the lung microvasculature. Pharmacologic or genetic disruption of serotonin uptake, or blockade of serotonin-dependent signaling, attenuated platelet activation and protected against respiratory distress, independently of viral replication and immune responses. Inhibition of fibrin formation similarly reduced disease severity, implicating serotonin-driven platelet procoagulant activity as a key contributor to age-related lung dysfunction. Thus, serotonin-mediated platelet procoagulant activity is a major contributor to respiratory insufficiency during SARS-CoV-2 infection and a potential therapeutic target for preserving pulmonary function, particularly in the elderly.
Authors
- Chiara Malpighi (ORCID: https://orcid.org/0000-0002-8325-0181)
- Marta Grillo (ORCID: https://orcid.org/0000-0001-9064-2274)
- Francesco Andreata (ORCID: https://orcid.org/0000-0002-5710-3671)
- Mauro Gaya (ORCID: https://orcid.org/0000-0002-7535-8678)
- Davide Marotta (ORCID: https://orcid.org/0000-0003-1918-050X)
- Mariangela Scavone (ORCID: https://orcid.org/0000-0002-8421-0210)
- Armando Tripodi (ORCID: https://orcid.org/0000-0003-1602-2776)
- Marigrazia Clerici (ORCID: https://orcid.org/0000-0002-0194-3962)
- Valeria Fumagalli (ORCID: https://orcid.org/0000-0003-2583-2498)
- Raffaele De Francesco (ORCID: https://orcid.org/0000-0001-8754-5123)
- Caitlin Abbott (ORCID: https://orcid.org/0000-0002-1024-1524)
- Lorena Donnici (ORCID: https://orcid.org/0000-0002-9153-9102)
- Marco De Giovanni (ORCID: https://orcid.org/0000-0001-7521-3092)
- Gian Marco Podda (ORCID: https://orcid.org/0000-0002-1791-8905)
- Donato Inverso (ORCID: https://orcid.org/0000-0003-0987-3345)
- Giulia D’Uonnolo (ORCID: https://orcid.org/0000-0002-7365-4406)
- Luca G. Guidotti (ORCID: https://orcid.org/0000-0002-0205-2678)
- Chiara Perucchini (ORCID: https://orcid.org/0000-0003-3010-8576)
- Jordan Rixon (ORCID: https://orcid.org/0000-0002-8313-0702)
- Erica Scalambrino (ORCID: https://orcid.org/0000-0001-6286-6924)
- Pietro Di Lucia (ORCID: https://orcid.org/0000-0002-0726-1532)
- Leonardo Giustini
- Violette Mouro (ORCID: https://orcid.org/0000-0002-4302-3662)
- Micol Ravà (ORCID: https://orcid.org/0000-0001-7606-8368)
- Zaverio M. Ruggeri (ORCID: https://orcid.org/0000-0003-0807-1295)
- Matteo Iannacone (ORCID: https://orcid.org/0000-0002-9370-2671)
- Natalia Stachura-Chyla
- Marika Longo Minnolo (ORCID: https://orcid.org/0009-0008-2034-2821)
Institutions
- Scripps Research Institute (US)
- Centre National de la Recherche Scientifique (FR)
- Vita-Salute San Raffaele University (IT)
- Inserm (FR)
- University of Milan (IT)
- Aix-Marseille Université (FR)
- Çağ University (TR)
- University of Gdańsk (PL)
- Ospedale San Paolo (IT)
- Ospedale L. Bonomo (IT)
- Centre d’Immunologie de Marseille-Luminy (FR)
- Istituto Nazionale Genetica Molecolare (IT)
Publication Details
- Journal
- Science Immunology
- Published
- 2026-08-28
- DOI
- https://doi.org/10.1126/sciimmunol.aec9853
- Primary Topic
- Platelet Disorders and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Horizon Therapeutics
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Associazione Italiana per la Ricerca sul Cancro
- European Research Council