title: 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.forename: Sebastian
authors.initials: S
authors.lastname: Vogel
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bodenstein
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Chen
authors.forename: Susanne
authors.initials: S
authors.lastname: Feil
authors.forename: Robert
authors.initials: R
authors.lastname: Feil
authors.forename: Johannes
authors.initials: J
authors.lastname: Rheinlaender
authors.forename: Tilman E
authors.initials: TE
authors.lastname: Schäffer
authors.forename: Erwin
authors.initials: E
authors.lastname: Bohn
authors.forename: Julia-Stefanie
authors.initials: JS
authors.lastname: Frick
authors.forename: Oliver
authors.initials: O
authors.lastname: Borst
authors.forename: Patrick
authors.initials: P
authors.lastname: Münzer
authors.forename: Britta
authors.initials: B
authors.lastname: Walker
authors.forename: Justin
authors.initials: J
authors.lastname: Markel
authors.forename: Gabor
authors.initials: G
authors.lastname: Csanyi
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Pagano
authors.forename: Patricia
authors.initials: P
authors.lastname: Loughran
authors.forename: Morgan E
authors.initials: ME
authors.lastname: Jessup
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Grant C
authors.initials: GC
authors.lastname: Bullock
authors.forename: Jason L
authors.initials: JL
authors.lastname: Sperry
authors.forename: Brian S
authors.initials: BS
authors.lastname: Zuckerbraun
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Neal
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D010974:Platelet Aggregation; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D006162:Guanylate Cyclase