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

Jessica R Hitchcock, Charlotte N Cook, Saeeda Bobat, Ewan A Ross, Adriana Flores-Langarica, Kate L Lowe, Mahmood Khan, Carmen Dominguez Medina, Sian Lax, Manuela Carvalho-Gaspar, Stefan Hubscher, George Rainger, Mark Cobbold, Christopher D Buckley, Tim J Mitchell, Andrea Mitchell, Nicholas Jones, N Van Rooijen, Daniel Kirchhofer, Ian R HendersonDavid H Adams, Steve P Watson, Adam F Cunningham

Research output: Contribution to journalArticlepeer-review

95 Citations (Scopus)
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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-γ release enhanced the number of podoplanin-expressing monocytes and Kupffer cells in the hepatic parenchyma and perivascular sites and absence of TLR4, IFN-γ, 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.

Original languageEnglish
Pages (from-to)4429–4446
JournalJournal of Clinical Investigation
Volume125
Issue number12
DOIs
Publication statusPublished - 16 Nov 2015

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