Platelet-derived HMGB1 is a critical mediator of thrombosis
| Autor: | Patrick J. Pagano, Patricia Loughran, Simon C. Watkins, Morgan Jessup, Rebecca Bodenstein, Grant C. Bullock, Qiwei Chen, Britta Walker, Tilman E. Schäffer, Erwin Bohn, Sebastian Vogel, Johannes Rheinlaender, Timothy R. Billiar, Justin Markel, Jason L. Sperry, Julia-Stefanie Frick, Meinrad Gawaz, Robert Feil, Gabor Csanyi, Patrick Münzer, Oliver Borst, Matthew D. Neal, Brian S. Zuckerbraun, Susanne Feil, Michael T. Lotze |
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| Rok vydání: | 2015 |
| Předmět: |
Blood Platelets
Platelet Aggregation Mice Transgenic chemical and pharmacologic phenomena Inflammation 030204 cardiovascular system & hematology HMGB1 Mice 03 medical and health sciences 0302 clinical medicine Mediator medicine Animals Platelet Platelet activation HMGB1 Protein Thrombus Blood Coagulation 030304 developmental biology Disseminated intravascular coagulation 0303 health sciences biology Cell Membrane Thrombosis General Medicine medicine.disease 3. Good health Toll-Like Receptor 4 Guanylate Cyclase Myeloid Differentiation Factor 88 Immunology biology.protein Cancer research medicine.symptom Research Article |
| Zdroj: | Journal of Clinical Investigation. 125:4638-4654 |
| ISSN: | 1558-8238 0021-9738 |
| Popis: | Thrombosis and inflammation are intricately linked in several major clinical disorders, including disseminated intravascular coagulation and acute ischemic events. The damage-associated molecular pattern molecule high-mobility group box 1 (HMGB1) is upregulated by activated platelets in multiple inflammatory diseases; however, the contribution of platelet-derived HMGB1 in thrombosis remains unexplored. Here, we generated transgenic mice with platelet-specific ablation of HMGB1 and determined that platelet-derived HMGB1 is a critical mediator of thrombosis. Mice lacking HMGB1 in platelets exhibited increased bleeding times as well as reduced thrombus formation, platelet aggregation, inflammation, and organ damage during experimental trauma/hemorrhagic shock. Platelets were the major source of HMGB1 within thrombi. In trauma patients, HMGB1 expression on the surface of circulating platelets was markedly upregulated. Moreover, evaluation of isolated platelets revealed that HMGB1 is critical for regulating platelet activation, granule secretion, adhesion, and spreading. These effects were mediated via TLR4- and MyD88-dependent recruitment of platelet guanylyl cyclase (GC) toward the plasma membrane, followed by MyD88/GC complex formation and activation of the cGMP-dependent protein kinase I (cGKI). Thus, we establish platelet-derived HMGB1 as an important mediator of thrombosis and identify a HMGB1-driven link between MyD88 and GC/cGKI in platelets. Additionally, these findings suggest a potential therapeutic target for patients sustaining trauma and other inflammatory disorders associated with abnormal coagulation. |
| Databáze: | OpenAIRE |
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