Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 125, Issue 12, Pages 4429-4446Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI79070
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Funding
- Medical Research Council [G0701275]
- Biotechnology and Biological Sciences Research Council [BB/F022778/1]
- Wellcome Trust [090244, 088410]
- British Heart Foundation [RG/13/18/30563]
- MRC
- Biotechnology and Biological Sciences Research Council [BB/L004461/1, BB/L009986/1, BB/F022778/1] Funding Source: researchfish
- British Heart Foundation [PG/13/40/30297, RG/13/18/30563, RG/12/7/29693] Funding Source: researchfish
- Medical Research Council [G0701275] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10080] Funding Source: researchfish
- Versus Arthritis [19791] Funding Source: researchfish
- BBSRC [BB/L009986/1, BB/L004461/1, BB/F022778/1] Funding Source: UKRI
- MRC [G0701275] Funding Source: UKRI
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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-gamma release enhanced the number of podoplanin-expressing monocytes and Kupffer cells in the hepatic parenchyma and perivascular sites and absence of TLR4, IFN-gamma, 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.
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