Inflammation drives thrombosis after Salmonella infection via CLEC-2 on platelets
Jessica R. Hitchcock, … , Steve P. Watson, Adam F. Cunningham
Jessica R. Hitchcock, … , Steve P. Watson, Adam F. Cunningham
Published November 16, 2015
Citation Information: J Clin Invest. 2015;125(12):4429-4446. https://doi.org/10.1172/JCI79070.
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Research Article Hematology

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-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.

Authors

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

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Figure 6

Podoplanin expression is elevated in the liver during infection.

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Podoplanin expression is elevated in the liver during infection. WT mice...
WT mice were infected i.p. as above for 7 days, and (A) podoplanin expression (green) was assessed in the liver alongside CD41 (red) and Hoechst (gray). (B) Podoplanin expression (blue) was examined with CD31 expression (green) in noninfected (top panel) and day 7–infected (bottom panel) sections; boxed areas are enlarged to the right-hand side. (C) Podoplanin (blue) expression by leukocytes was examined alongside CD41 (green), CD45.2 (red), and Hoechst (gray). (D) Podoplanin expression (blue) by stromal populations was examined alongside CD31 (green), CD248 (red), and Hoechst (gray). All images were obtained from frozen liver sections by fluorescent confocal microscopy. Scale bars: 100 μm unless indicated otherwise. LV, lymphatic vessel. Images are representative of ≥ 3 experiments with ≥ 4 mice in each group.