Pharmacological inhibition of type I interferon signaling protects mice against lethal sepsis.
Current research on new therapeutic strategies for sepsis uses different animal models, such as the lipopolysaccharide-induced endotoxemia model and the cecal ligation and puncture (CLP) peritonitis model. By using genetic and pharmacologic inhibition of the type I interferon (IFN) receptor (IFNAR1), we show that type I IFN signaling plays a detrimental role in these sepsis models. Mortality after CLP was reduced even when type I IFN responses were blocked after the onset of sepsis. Our findings reveal that type I IFNs play an important detrimental role during sepsis by negatively regulating neutrophil recruitment. Reduced neutrophil influx likely occurs via the induction of the CXC motif chemokine 1. Moreover, human white blood cells exposed to heat-killed Pseudomonas aeruginosa secrete IFN-β and stimulate type I IFN signaling. We provide data that support pharmacologic inhibition of type I IFN signaling as a novel therapeutic treatment in severe sepsis.
Inflammation Research Center, Flanders Institute for Biotechnology.
Lien
L
Dejager
Sofie
S
Vandevyver
Marlies
M
Ballegeer
Elien
E
Van Wonterghem
Ling-Ling
LL
An
Jeffrey
J
Riggs
Roland
R
Kolbeck
Claude
C
Libert
D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016470:Bacteremia / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D002432:Cecum / Q000293:injuries / Q000601:surgery; D019446:Endotoxemia / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology*
D000911:Antibodies, Monoclonal; C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta
cecal ligation and puncture; endotoxemia; neutrophils; sepsis; type I interferons