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.

Mice with a deficiency in CLEC-2 are protected against deep vein thrombosis

“…The key role of CLEC-2 in thrombosis in inflammatory settings has recently been reported. 38 This study demonstrated that after infection with Salmonella, extensive thrombosis develops in the liver of control mice through an inflammationdriven pathway in a CLEC-2-dependent fashion. Thrombosis induced by the bacteria was associated with upregulation of podoplanin.…”

“…A similar unique impact of CLEC-2 has been demonstrated in Salmonella infection-induced thrombosis; this is independent of GPVI. 38 Marked upregulation of podoplanin in the IVC wall induced by stenosis may promote its interaction with CLEC-2. The importance of the extent of podoplanin expression elevation following stenosis is confirmed by direct association between the magnitude of this elevation and incidence of thrombosis.…”

“…Its expression has been confirmed in lymphatic endothelium, glomerular podocytes in kidneys, type I alveolar cells in lungs, and in several types of cancers, but not in vascular endothelium. 2 However, upregulation of podoplanin in the tissues adjacent to blood vasculature has been reported in the Salmonella-mediated inflammation model, 38 and CLEC-2/podoplanin interactions have been shown to secure vessel wall in high endothelial venules. 41 We demonstrate here that podoplanin is present in the IVC wall.…”

Hematopoietic stem cell loss and hematopoietic failure in severe aplastic anemia is driven by macrophages and aberrant podoplanin expression

“…49 PDPN is a CLEC-2 ligand that triggers downstream signaling in CLEC2-expressing cells. However CLEC-2/PDPN ligation also elicits bidirectional signaling, eliciting RANTES production from PDPN-expressing cells.…”

Risking thromboembolism: podoplanin and glioma

“…It is interesting to note that myc overexpression via amplification or translocation induces cytoprotective autophagy via the PERK/eIF2a/ATF4 pathway in lymphoma, and inhibition of autophagy in the same model leads to mycdependent cell death. 9 Although further studies are warranted, the fact that myc-driven lymphoma could potentially exploit this pathway to escape stressful conditions provides the rationale for a dual approach with apilimod and chemotherapy specifically in myc-driven lymphomas. (2) Risking thromboembolism: podoplanin and glioma…”