Journal article
Platelet-derived HMGB1 is a critical mediator of thrombosis
The Journal of clinical investigation, Vol.125(12), pp.4638-4654
12/01/2015
DOI: 10.1172/JCI81660
PMCID: PMC4665785
PMID: 26551681
Abstract
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.
Details
- Title: Subtitle
- Platelet-derived HMGB1 is a critical mediator of thrombosis
- Creators
- Sebastian Vogel - University of TübingenRebecca Bodenstein - University of TübingenQiwei Chen - University of PittsburghSusanne Feil - University of TübingenRobert Feil - University of TübingenJohannes Rheinlaender - Institute of Applied PhysicsTilman E. Schaeffer - University of TübingenErwin Bohn - Institute of Medical Microbiology and HygieneJulia-Stefanie Frick - Institute of Medical Microbiology and HygieneOliver Borst - University of TübingenPatrick Muenzer - University of TübingenBritta Walker - University of TübingenJustin Markel - University of PittsburghGabor Csanyi - University of PittsburghPatrick J. Pagano - University of PittsburghPatricia Loughran - University of PittsburghMorgan E. Jessup - University of PittsburghSimon C. Watkins - University of PittsburghGrant C. Bullock - University of PittsburghJason L. Sperry - University of PittsburghBrian S. Zuckerbraun - University of PittsburghTimothy R. Billiar - University of PittsburghMichael T. Lotze - University of PittsburghMeinrad Gawaz - University of TübingenMatthew D. Neal - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.125(12), pp.4638-4654
- Publisher
- Amer Soc Clinical Investigation Inc
- DOI
- 10.1172/JCI81660
- PMID
- 26551681
- PMCID
- PMC4665785
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Number of pages
- 17
- Grant note
- P50GM053789; 1S10OD019973-01 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01HL079207; UM1HL120877; R00HL114648 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) American Association for the Surgery of Trauma Research Scholarship Department of Cardiology and Cardiovascular Diseases of the University of Tubingen Klinische Forschergruppe 274; VO 2126/1-1; GA 381/10-2; FE 438/7-1; SCHA 1264/2-2 / Deutsche Forschungsgemeinschaft (DFG); German Research Foundation (DFG) P50GM053789 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) Department of Surgery of the University of Pittsburgh S10OD019973 / OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P30CA047904 / University of Pittsburgh Cancer Institute core support from the National Cancer Institute UM1 HL120877-01 / Trans-Agency Consortium for Trauma-Induced Coagulopathy P30CA047904 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) UL1TR000005 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS)
- Language
- English
- Date published
- 12/01/2015
- Academic Unit
- Pathology
- Record Identifier
- 9984697641102771
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