title: 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.forename: Jessica R
authors.initials: JR
authors.lastname: Hitchcock
authors.forename: Charlotte N
authors.initials: CN
authors.lastname: Cook
authors.forename: Saeeda
authors.initials: S
authors.lastname: Bobat
authors.forename: Ewan A
authors.initials: EA
authors.lastname: Ross
authors.forename: Adriana
authors.initials: A
authors.lastname: Flores-Langarica
authors.forename: Kate L
authors.initials: KL
authors.lastname: Lowe
authors.forename: Mahmood
authors.initials: M
authors.lastname: Khan
authors.forename: C Coral
authors.initials: CC
authors.lastname: Dominguez-Medina
authors.forename: Sian
authors.initials: S
authors.lastname: Lax
authors.forename: Manuela
authors.initials: M
authors.lastname: Carvalho-Gaspar
authors.forename: Stefan
authors.initials: S
authors.lastname: Hubscher
authors.forename: G Ed
authors.initials: GE
authors.lastname: Rainger
authors.forename: Mark
authors.initials: M
authors.lastname: Cobbold
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Mitchell
authors.forename: Andrea
authors.initials: A
authors.lastname: Mitchell
authors.forename: Nick D
authors.initials: ND
authors.lastname: Jones
authors.forename: N
authors.initials: N
authors.lastname: Van Rooijen
authors.forename: Daniel
authors.initials: D
authors.lastname: Kirchhofer
authors.forename: Ian R
authors.initials: IR
authors.lastname: Henderson
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cunningham
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D012480:Salmonella Infections / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012486:Salmonella typhimurium / Q000378:metabolism*; D013927:Thrombosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: C529518:CLEC-2 protein, mouse; D037181:Lectins, C-Type; D010980:Platelet Membrane Glycoproteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C098341:platelet membrane glycoprotein VI; D007371:Interferon-gamma