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Stark, K.* ; Philippi, V.* ; Stockhausen, S.* ; Busse, J.* ; Antonelli, A.* ; Miller, M.* ; Schubert, I.* ; Hoseinpour, P.* ; Chandraratne, S.* ; von Brühl, M.L.* ; Gärtner, F.* ; Lorenz, M.* ; Agresti, A.* ; Coletti, R.* ; Antoine, D.J.* ; Heermann, R.* ; Jung, K.* ; Reese, S.* ; Laitinen, I.* ; Schwaiger, M.* ; Walch, A.K. ; Sperandio, M.* ; Nawroth, P.P.* ; Reinhardt, C.* ; Jäckel, S.* ; Bianchi, M.E.* ; Massberg, S.*

Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice.

Blood 128, 2435-2449 (2016)
Publ. Version/Full Text Postprint Research data DOI PMC
Open Access Green
Deep venous thrombosis (DVT) is one of the most common cardiovascular diseases, but its pathophysiology remains incompletely understood. While 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 RAGE and TLR2, 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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Mobility Group Box-1; Glycation End-products; Neutrophil Extracellular Traps; Green Fluorescent Protein; Deep-vein Thrombosis; Sterile Inflammation; Innate Immunity; In-vivo; Dependent Mechanisms; Ischemia-reperfusion
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Journal Blood
Quellenangaben Volume: 128, Issue: 20, Pages: 2435-2449 Article Number: , Supplement: ,
Publisher American Society of Hematology
Publishing Place Washington
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Analytical Pathology (AAP)