Platelet-derived HMGB1 is a critical mediator of thrombosis

Sebastian Vogel, Rebecca Bodenstein, Qiwei Chen, Susanne Feil, Robert Feil, Johannes Rheinlaender, Tilman E. Schäffer, Erwin Bohn, Julia Stefanie Frick, Oliver Borst, Patrick Münzer, Britta Walker, Justin Markel, Gabor Csanyi, Patrick J. Pagano, Patricia Loughran, Morgan E. Jessup, Simon C. Watkins, Grant C. Bullock, Jason L. Sperry & 5 others Brian S. Zuckerbraun, Timothy R. Billiar, Michael T. Lotze, Meinrad Gawaz, Matthew D. Neal

Research output: Contribution to journalArticle

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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 plateletderived 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.

Original languageEnglish (US)
Pages (from-to)4638-4654
Number of pages17
JournalJournal of Clinical Investigation
Volume125
Issue number12
DOIs
StatePublished - Dec 1 2015

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Thrombosis
Blood Platelets
Cyclic GMP-Dependent Protein Kinase Type I
Guanylate Cyclase
Wounds and Injuries
Inflammation
Bleeding Time
Hemorrhagic Shock
Disseminated Intravascular Coagulation
Platelet Activation
Platelet Aggregation
Transgenic Mice
Cell Membrane

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Vogel, S., Bodenstein, R., Chen, Q., Feil, S., Feil, R., Rheinlaender, J., ... Neal, M. D. (2015). Platelet-derived HMGB1 is a critical mediator of thrombosis. Journal of Clinical Investigation, 125(12), 4638-4654. https://doi.org/10.1172/JCI81660

Platelet-derived HMGB1 is a critical mediator of thrombosis. / Vogel, Sebastian; Bodenstein, Rebecca; Chen, Qiwei; Feil, Susanne; Feil, Robert; Rheinlaender, Johannes; Schäffer, Tilman E.; Bohn, Erwin; Frick, Julia Stefanie; Borst, Oliver; Münzer, Patrick; Walker, Britta; Markel, Justin; Csanyi, Gabor; Pagano, Patrick J.; Loughran, Patricia; Jessup, Morgan E.; Watkins, Simon C.; Bullock, Grant C.; Sperry, Jason L.; Zuckerbraun, Brian S.; Billiar, Timothy R.; Lotze, Michael T.; Gawaz, Meinrad; Neal, Matthew D.

In: Journal of Clinical Investigation, Vol. 125, No. 12, 01.12.2015, p. 4638-4654.

Research output: Contribution to journalArticle

Vogel, S, Bodenstein, R, Chen, Q, Feil, S, Feil, R, Rheinlaender, J, Schäffer, TE, Bohn, E, Frick, JS, Borst, O, Münzer, P, Walker, B, Markel, J, Csanyi, G, Pagano, PJ, Loughran, P, Jessup, ME, Watkins, SC, Bullock, GC, Sperry, JL, Zuckerbraun, BS, Billiar, TR, Lotze, MT, Gawaz, M & Neal, MD 2015, 'Platelet-derived HMGB1 is a critical mediator of thrombosis', Journal of Clinical Investigation, vol. 125, no. 12, pp. 4638-4654. https://doi.org/10.1172/JCI81660
Vogel S, Bodenstein R, Chen Q, Feil S, Feil R, Rheinlaender J et al. Platelet-derived HMGB1 is a critical mediator of thrombosis. Journal of Clinical Investigation. 2015 Dec 1;125(12):4638-4654. https://doi.org/10.1172/JCI81660
Vogel, Sebastian ; Bodenstein, Rebecca ; Chen, Qiwei ; Feil, Susanne ; Feil, Robert ; Rheinlaender, Johannes ; Schäffer, Tilman E. ; Bohn, Erwin ; Frick, Julia Stefanie ; Borst, Oliver ; Münzer, Patrick ; Walker, Britta ; Markel, Justin ; Csanyi, Gabor ; Pagano, Patrick J. ; Loughran, Patricia ; Jessup, Morgan E. ; Watkins, Simon C. ; Bullock, Grant C. ; Sperry, Jason L. ; Zuckerbraun, Brian S. ; Billiar, Timothy R. ; Lotze, Michael T. ; Gawaz, Meinrad ; Neal, Matthew D. / Platelet-derived HMGB1 is a critical mediator of thrombosis. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 12. pp. 4638-4654.
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AU - Vogel, Sebastian

AU - Bodenstein, Rebecca

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AU - Rheinlaender, Johannes

AU - Schäffer, Tilman E.

AU - Bohn, Erwin

AU - Frick, Julia Stefanie

AU - Borst, Oliver

AU - Münzer, Patrick

AU - Walker, Britta

AU - Markel, Justin

AU - Csanyi, Gabor

AU - Pagano, Patrick J.

AU - Loughran, Patricia

AU - Jessup, Morgan E.

AU - Watkins, Simon C.

AU - Bullock, Grant C.

AU - Sperry, Jason L.

AU - Zuckerbraun, Brian S.

AU - Billiar, Timothy R.

AU - Lotze, Michael T.

AU - Gawaz, Meinrad

AU - Neal, Matthew D.

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N2 - 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 plateletderived 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.

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