{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T14:05:19Z","timestamp":1791813919300,"version":"4.3.4"},"reference-count":52,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T00:00:00Z","timestamp":1763164800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"NHBLI","doi-asserted-by":"crossref","award":["K08HL153784"],"award-info":[{"award-number":["K08HL153784"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"crossref","award":["R01AI192405"],"award-info":[{"award-number":["R01AI192405"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Sepsis is a clinical syndrome caused by abnormal host response to infection. Thrombocytopenia and platelet dysfunction are common findings in sepsis and associated with worse outcomes. The innate immune single-stranded RNA sensor, Toll-like Receptor-7 (TLR7), plays a key role in thrombocytopenia in sepsis. This study investigated whether TLR7 signaling also contributes to platelet dysfunction in sepsis, and whether the bioactivity of downstream inflammatory mediators, specifically extracellular vesicles (EVs), is impacted by the TLR7 signaling pathway. Sepsis was induced in wild-type (WT) and TLR7-deficient (TLR7\u2212\/\u2212) mice by cecal ligation and puncture. Blood was collected at twenty-four hours for platelet and plasma isolation, and platelet function was assessed using aggregation, adhesion, and calcium flux assays. EVs were isolated from plasma and used in vitro to evaluate their impact on platelet\u2013leukocyte aggregate (PLA) formation. We found that septic platelets are highly activated and more adhesive, yet show markedly impaired aggregation and reduced calcium signaling, indicating functional exhaustion despite activation. Notably, mice lacking TLR7 maintained stronger platelet aggregation, enhanced adhesion, and preserved calcium release in the septic state compared to wild-type controls, suggesting a protective effect of TLR7 deficiency. Plasma EVs increased in abundance and size during sepsis and promoted clot and PLA formation in vitro. Notably, EV-mediated platelet activation was reduced with EVs derived from TLR7-deficient mice. Our results demonstrate that while sepsis drives persistent platelet activation and dysfunction, TLR7 deficiency preserves platelet function and modulates the pathogenic activity of EV-mediated platelet activation, highlighting TLR7 as a key regulator and potential therapeutic target in sepsis-induced platelet dysfunction.<\/jats:p>","DOI":"10.3390\/biom15111604","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T14:04:07Z","timestamp":1763388247000},"page":"1604","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Toll-like Receptor 7 Deficiency Attenuates Platelet Dysfunction in Sepsis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4808-6284","authenticated-orcid":false,"given":"Rashida","family":"Mohamed-Hinds","sequence":"first","affiliation":[{"name":"Translational Research Program, Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3209-8391","authenticated-orcid":false,"given":"Arijit","family":"Dutta","sequence":"additional","affiliation":[{"name":"Translational Research Program, Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanhee","family":"Park","sequence":"additional","affiliation":[{"name":"Translational Research Program, Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4081-4207","authenticated-orcid":false,"given":"Xiaomei","family":"Yang","sequence":"additional","affiliation":[{"name":"Translational Research Program, Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Zou","sequence":"additional","affiliation":[{"name":"Translational Research Program, Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2505-1360","authenticated-orcid":false,"given":"Wei","family":"Chao","sequence":"additional","affiliation":[{"name":"Translational Research Program, Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittney","family":"Williams","sequence":"additional","affiliation":[{"name":"Translational Research Program, Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13613-022-01093-7","article-title":"The prevalence of sepsis-induced coagulopathy in patients with sepsis\u2014A secondary analysis of two German multicenter randomized controlled trials","volume":"13","author":"Schmoch","year":"2023","journal-title":"Ann. 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