Platelet-derived HMGB1 is a critical mediator of thrombosis
Sebastian Vogel, … , Meinrad Gawaz, Matthew D. Neal
Sebastian Vogel, … , Meinrad Gawaz, Matthew D. Neal
Published November 9, 2015
Citation Information: J Clin Invest. 2015;125(12):4638-4654. https://doi.org/10.1172/JCI81660.
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Platelet-derived HMGB1 is a critical mediator of thrombosis

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.

Authors

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, Brian S. Zuckerbraun, Timothy R. Billiar, Michael T. Lotze, Meinrad Gawaz, Matthew D. Neal

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Figure 7

HMGB1 induces MyD88-dependent recruitment of GC to the platelet plasma membrane, MyD88/GC complex formation, and cGMP production in platelets.

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HMGB1 induces MyD88-dependent recruitment of GC to the platelet plasma m...
Detection of intracellular (A) MyD88 and (A and B) GC in isolated (A) human and (B) murine (WT, Myd88–/–) platelets by immunofluorescence staining and confocal laser scanning microscopy. (A) Treatment of human platelets with HMGB1 or LPS induces translocation of MyD88 and GC toward the plasma membrane in platelets, whereas untreated and DEA/NO-treated platelets show a uniform intracellular distribution of MyD88 and GC. Scale bar: 5 μm (top 3 rows), 1 μm (bottom row). (B) HMGB1 also induces translocation of GC toward the plasma membrane in murine WT platelets, which does not occur in Myd88–/– platelets. Scale bar: 5 μm (top row), 1 μm (bottom row). (C–F) Coimmunoprecipitation studies reveal HMGB1-dependent complex formation of MyD88 and GC in murine platelets. (G) HMGB1 treatment induces cGMP production in WT platelets, which does not occur in Myd88–/– platelets. Data show mean ± SD of the results from at least 3 separate experiments and n ≥ 3 mice per group.