title: Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice.
abstract: Deep venous thrombosis (DVT) is one of the most common cardiovascular diseases, but its pathophysiology remains incompletely understood. Although sterile inflammation has recently been shown to boost coagulation during DVT, the underlying molecular mechanisms are not fully resolved, which could potentially identify new anti-inflammatory approaches to prophylaxis and therapy of DVT. Using a mouse model of venous thrombosis induced by flow reduction in the vena cava inferior, we identified blood-derived high-mobility group box 1 protein (HMGB1), a prototypical mediator of sterile inflammation, to be a master regulator of the prothrombotic cascade involving platelets and myeloid leukocytes fostering occlusive DVT formation. Transfer of platelets into Hmgb1-/-chimeras showed that this cell type is the major source of HMGB1, exposing reduced HMGB1 on their surface upon activation thereby enhancing the recruitment of monocytes. Activated leukocytes in turn support oxidation of HMGB1 unleashing its prothrombotic activity and promoting platelet aggregation. This potentiates the amount of HMGB1 and further nurtures the accumulation and activation of monocytes through receptor for advanced glycation end products (RAGE) and Toll-like receptor 2, leading to local delivery of monocyte-derived tissue factor and cytokines. Moreover, disulfide HMGB1 facilitates formation of prothrombotic neutrophil extracellular traps (NETs) mediated by RAGE, exposing additional HMGB1 on their extracellular DNA strands. Eventually, a vicious circle of coagulation and inflammation is set in motion leading to obstructive DVT formation. Therefore, platelet-derived disulfide HMGB1 is a central mediator of the sterile inflammatory process in venous thrombosis and could be an attractive target for an anti-inflammatory approach for DVT prophylaxis.
authors: Medizinische Klinik I, Ludwig-Maximilians-Universität, Munich, Germany.|German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany.
authors: Konstantin
authors: K
authors: Stark
authors: Medizinische Klinik I, Ludwig-Maximilians-Universität, Munich, Germany.
authors: Vanessa
authors: V
authors: Philippi
authors: Medizinische Klinik I, Ludwig-Maximilians-Universität, Munich, Germany.
authors: Sven
authors: S
authors: Stockhausen
authors: Medizinische Klinik I, Ludwig-Maximilians-Universität, Munich, Germany.
authors: Johanna
authors: J
authors: Busse
authors: Chromatin Dynamics Unit, San Raffaele University and Scientific Institute, Milan, Italy.
authors: Antonella
authors: A
authors: Antonelli
authors: Medizinische Klinik I, Ludwig-Maximilians-Universität, Munich, Germany.
authors: Meike
authors: M
authors: Miller
authors: Medizinische Klinik I, Ludwig-Maximilians-Universität, Munich, Germany.
authors: Irene
authors: I
authors: Schubert
authors: Medizinische Klinik I, Ludwig-Maximilians-Universität, Munich, Germany.
authors: Parandis
authors: P
authors: Hoseinpour
authors: Medizinische Klinik I, Ludwig-Maximilians-Universität, Munich, Germany.
authors: Sue
authors: S
authors: Chandraratne
authors: Medizinische Klinik I, Ludwig-Maximilians-Universität, Munich, Germany.
authors: Marie-Luise
authors: ML
authors: von Brühl
authors: Medizinische Klinik I, Ludwig-Maximilians-Universität, Munich, Germany.|German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany.
authors: Florian
authors: F
authors: Gaertner
authors: Medizinische Klinik I, Ludwig-Maximilians-Universität, Munich, Germany.
authors: Michael
authors: M
authors: Lorenz
authors: Chromatin Dynamics Unit, San Raffaele University and Scientific Institute, Milan, Italy.
authors: Alessandra
authors: A
authors: Agresti
authors: Medizinische Klinik I, Ludwig-Maximilians-Universität, Munich, Germany.
authors: Raffaele
authors: R
authors: Coletti
authors: Medical Research Council Center for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors: Daniel J
authors: DJ
authors: Antoine
authors: Munich Center for Integrated Protein Science, Department of Biology I, and.
authors: Ralf
authors: R
authors: Heermann
authors: Munich Center for Integrated Protein Science, Department of Biology I, and.
authors: Kirsten
authors: K
authors: Jung
authors: Lehrstuhl für Anatomie, Histologie und Embryologie, Faculty of Veterinary Medicine, Ludwig-Maximilians Universität, Munich, Germany.
authors: Sven
authors: S
authors: Reese
authors: Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors: Iina
authors: I
authors: Laitinen
authors: Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors: Markus
authors: M
authors: Schwaiger
authors: Helmholtz Zentrum München, Deutsches Forschungszentrum für Umwelt und Gesundheit, Institut für Pathologie, Neuherberg, Germany.
authors: Axel
authors: A
authors: Walch
authors: German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany.|Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany.
authors: Markus
authors: M
authors: Sperandio
authors: Department of Internal Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany.
authors: Peter P
authors: PP
authors: Nawroth
authors: Center for Thrombosis and Hemostasis University Medical Center Mainz, Mainz, Germany; and.|German Center for Cardiovascular Research, Partner Site RheinMain, Mainz, Germany.
authors: Christoph
authors: C
authors: Reinhardt
authors: Center for Thrombosis and Hemostasis University Medical Center Mainz, Mainz, Germany; and.|German Center for Cardiovascular Research, Partner Site RheinMain, Mainz, Germany.
authors: Sven
authors: S
authors: Jäckel
authors: Chromatin Dynamics Unit, San Raffaele University and Scientific Institute, Milan, Italy.
authors: Marco E
authors: ME
authors: Bianchi
authors: Medizinische Klinik I, Ludwig-Maximilians-Universität, Munich, Germany.|German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany.
authors: Steffen
authors: S
authors: Massberg
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D024243:HMGB1 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics; D020246:Venous Thrombosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D004220:Disulfides; D024243:HMGB1 Protein; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D000067759:Receptor for Advanced Glycation End Products; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4