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Gut microbiota regulate hepatic von Willebrand factor synthesis and arterial thrombus formation via Toll-like receptor-2.

Authors: Jäckel, Sven  Kiouptsi, Klytaimnistra  Lillich, Maren  Hendrikx, Tim  Khandagale, Avinash  Kollar, Bettina  Hörmann, Nives  Reiss, Cora  Subramaniam, Saravanan  Wilms, Eivor  Ebner, Katharina  Brühl, Marie-Luise von  Rausch, Philipp  Baines, John F  Haberichter, Sandra  Lämmle, Bernhard  Binder, Christoph J  Jurk, Kerstin  Ruggeri, Zaverio M  Massberg, Steffen  Walter, Ulrich  Ruf, Wolfram  Reinhardt, Christoph 
Citation: Jäckel S, etal., Blood. 2017 Jul 27;130(4):542-553. doi: 10.1182/blood-2016-11-754416. Epub 2017 Jun 1.
Pubmed: (View Article at PubMed) PMID:28572286
DOI: Full-text: DOI:10.1182/blood-2016-11-754416

The symbiotic gut microbiota play pivotal roles in host physiology and the development of cardiovascular diseases, but the microbiota-triggered pattern recognition signaling mechanisms that impact thrombosis are poorly defined. In this article, we show that germ-free (GF) and Toll-like receptor-2 (Tlr2)-deficient mice have reduced thrombus growth after carotid artery injury relative to conventionally raised controls. GF Tlr2 -/- and wild-type (WT) mice were indistinguishable, but colonization with microbiota restored a significant difference in thrombus growth between the genotypes. We identify reduced plasma levels of von Willebrand factor (VWF) and reduced VWF synthesis, specifically in hepatic endothelial cells, as a critical factor that is regulated by gut microbiota and determines thrombus growth in Tlr2 -/- mice. Static platelet aggregate formation on extracellular matrix was similarly reduced in GF WT, Tlr2 -/- , and heterozygous Vwf +/- mice that are all characterized by a modest reduction in plasma VWF levels. Defective platelet matrix interaction can be restored by exposure to WT plasma or to purified VWF depending on the VWF integrin binding site. Moreover, administration of VWF rescues defective thrombus growth in Tlr2 -/- mice in vivo. These experiments delineate an unexpected pathway in which microbiota-triggered TLR2 signaling alters the synthesis of proadhesive VWF by the liver endothelium and favors platelet integrin-dependent thrombus growth.

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CRRD Object Information
CRRD ID: 15090824
Created: 2019-12-20
Species: All species
Last Modified: 2019-12-20
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.