Platelet-mediated activation of perivascular mast cells triggers progression of sepsis to septic shock in mice

The critical events that trigger sepsis progression into life-threatening septic shock remain unclear. In agreement with reports that link a drop in platelet count to a complicated clinical course in sepsis patients, here we report that, during sepsis, mouse platelets become activated, deposit systemically on vascular walls, and stimulate perivascular mast cells (MC) by releasing platelet activating factor (PAF). In mouse models and patient samples, MC activation correlates with the development of shock in sepsis and is mechanistically linked to shock by inducing systemic hypotension, vascular leakage and microvascular perfusion abnormalities. Preventing platelet or MC activation, or inhibiting the activity of the major MC granule constituent chymase, averts progression from sepsis to shock and reduces mortality of septic mice. Thus, our work establishes that, during sepsis progression, platelet microvascular adhesion leads to MC-mediated vascular changes to culminate in septic shock and septic shock-associated mortality.

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Publication Details

Journal
Nature Communications
Published
2025-12-03
DOI
https://doi.org/10.1038/s41467-025-66978-0
Primary Topic
Mast cells and histamine
Type
article
Field-Weighted Citation Impact
0.00

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article

Platelet-mediated activation of perivascular mast cells triggers progression of sepsis to septic shock in mice

Junjie Yao, Cassandra Fiorino, Hae Woong Choi, Ephraim L. Tsalik et al.
Nature Communications
Mast cells and histamine
article

Platelet-mediated activation of perivascular mast cells triggers progression of sepsis to septic shock in mice

Junjie Yao, Cassandra Fiorino, Hae Woong Choi, Ephraim L. Tsalik, Mathew Abraham, Jason A. Iskarpatyoti, Soman N. Abraham, Jörn Karhausen, Chunjing Bao, Ulrike Hoffmann, Jamie R. Privratsky, Wolfgang Bergmeier, Joo Hwan Noh, Robert H. Lee, Xiaoyi Zhu
article en

Abstract

The critical events that trigger sepsis progression into life-threatening septic shock remain unclear. In agreement with reports that link a drop in platelet count to a complicated clinical course in sepsis patients, here we report that, during sepsis, mouse platelets become activated, deposit systemically on vascular walls, and stimulate perivascular mast cells (MC) by releasing platelet activating factor (PAF). In mouse models and patient samples, MC activation correlates with the development of shock in sepsis and is mechanistically linked to shock by inducing systemic hypotension, vascular leakage and microvascular perfusion abnormalities. Preventing platelet or MC activation, or inhibiting the activity of the major MC granule constituent chymase, averts progression from sepsis to shock and reduces mortality of septic mice. Thus, our work establishes that, during sepsis progression, platelet microvascular adhesion leads to MC-mediated vascular changes to culminate in septic shock and septic shock-associated mortality.

Nature CommunicationsVol. 17(1)
University of North Carolina at Chapel Hill (US), National University of Singapore (SG), Duke University (US), Korea University (KR), Danaher (United States) (US), Duke Medical Center (US), Duke University Hospital (US), IRCCS Humanitas Research Hospital (IT)
National Science Foundation, American Heart Association, National Research Foundation, Korea University, National Research Foundation of Korea, National Institutes of Health
Openalex Percentile: Top 57%
Mast cells and histamine
DOIOpen Access PDFOpenAlex
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