A Translational Investigation of Interferon-α and STAT1 Signaling in Endothelial Cells during Septic Shock Provides Therapeutic Perspectives.
Fiche publication
Date publication
avril 2021
Journal
American journal of respiratory cell and molecular biology
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BAHRAM Siamak
Tous les auteurs :
Clere-Jehl R, Merdji H, Kassem M, Macquin C, De Cauwer A, Sibony A, Kurihara K, Minniti L, Abou Fayçal C, Bahram S, Meziani F, Helms J, Georgel P
Lien Pubmed
Résumé
Septic shock and disseminated intravascular coagulation (DIC) are knowingly characterized by an endothelial cell dysfunction. The molecular mechanisms underlying this relationship are, however, poorly understood. In this work, me aimed at investigating human circulating interferon-α (IFN-α) in septic shock-induced DIC patients and tested the potential role of endothelial Stat1 as a therapeutic target in a mouse model of sepsis. For this, circulating type I, II and III IFNs and procoagulant microvesicles were quantified in a prospective cohort of septic shock patients. Next, we used a septic shock model induced by cecal ligation and puncture (CLP) in wild-type (WT) mice, in Ifnar1 (type I IFN receptor subunit 1)-knockout (KO) mice, as well as in Stat1 (Signal transducer and activator of transcription 1) conditional KO mice. In humans samples, we observed higher levels of circulating IFN-α and IFN-α1 in DIC compared to non-DIC patients, while levels of IFN-β, IFN-γ, IFN-λ1, IFN-λ2, IFN-λ3 were not different. IFN-α level was positively correlated with CD105-microvesicle levels, reflecting endothelial injury. In Ifnar1-/- mice, CLP did not induce septic shock and was characterized by lesser endothelial cell injury, with lower aortic inflammatory cytokine expression, endothelial inflammatory-related genes expression and fibrinolysis. In mice in which Stat1 was specifically ablated in endothelial cells, a marked protection against sepsis was also observed, suggesting the relevance of an endothelium-targeted strategy. Our work highlights the key roles of type I interferons as pathogenic players in septic shock-induced DIC and the potential pertinence of endothelial STAT1 as a therapeutic target.
Mots clés
sepsis , endothelium , disseminated intravascular coagulation , interferons , STAT transcription factors
Référence
Am J Respir Cell Mol Biol. 2021 Apr 2;: