Inflammation drives thrombosis after Salmonella infection via CLEC-2 on platelets

Abstract

Thrombosis is a common, life-threatening consequence of systemic infection; however, the underlying mechanisms that drive the formation of infection-associated thrombi are poorly understood. Here, using a mouse model of systemic Salmonella Typhimurium infection, we determined that inflammation in tissues triggers thrombosis within vessels via ligation of C-type lectin-like receptor-2 (CLEC-2) on platelets by podoplanin exposed to the vasculature following breaching of the vessel wall. During infection, mice developed thrombi that persisted for weeks within the liver. Bacteria triggered but did not maintain this process, as thrombosis peaked at times when bacteremia was absent and bacteria in tissues were reduced by more than 90% from their peak levels. Thrombus development was triggered by an innate, TLR4-dependent inflammatory cascade that was independent of classical glycoprotein VI-mediated (GPVI-mediated) platelet activation. After infection, IFN-ã release enhanced the number of podoplanin-expressing monocytes and Kupffer cells in the hepatic parenchyma and perivascular sites and absence of TLR4, IFN-ã, or depletion of monocytic-lineage cells or CLEC-2 on platelets markedly inhibited the process. Together, our data indicate that infection-driven thrombosis follows local inflammation and upregulation of podoplanin and platelet activation. The identification of this pathway offers potential therapeutic opportunities to control the devastating consequences of infection-driven thrombosis without increasing the risk of bleeding.

Publication DOI: https://doi.org/10.1172/JCI79070
Divisions: College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences
Additional Information: J Clin Invest. 2015;125(12):4429-4446. https://doi.org/10.1172/JCI79070.
Uncontrolled Keywords: Medicine(all)
Publication ISSN: 1558-8238
Last Modified: 27 May 2024 07:31
Date Deposited: 28 Aug 2019 14:06
Full Text Link:
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
https://www.jci ... cles/view/79070 (Publisher URL)
PURE Output Type: Article
Published Date: 2015-12-01
Authors: Hitchcock, Jessica R.
Cook, Charlotte N.
Bobat, Saeeda
Ross, Ewan A. (ORCID Profile 0000-0001-5733-9361)
Flores-Langarica, Adriana
Lowe, Kate L.
Khan, Mahmood
Coral Dominguez-Medina, C.
Lax, Sian
Carvalho-Gaspar, Manuela
Hubscher, Stefan
Ed Rainger, G.
Cobbold, Mark
Buckley, Christopher D.
Mitchell, Tim J.
Mitchell, Andrea
Jones, Nick D.
Van Rooijen, N.
Kirchhofer, Daniel
Henderson, Ian R.
Adams, David H.
Watson, Steve P.
Cunningham, Adam F.

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