Type I IFN modulates host defense and late hyperinflammation in septic peritonitis

(2006)

Publication Type: Journal article

Publication year: 2006

Journal

Journal of Immunology American Association of Immunologists

Book Volume: 177

Pages Range: 5623-5630

Journal Issue: 8

DOI: 10.4049/jimmunol.177.8.5623

Abstract

TLRs are considered important for the control of immune responses during endotoxic shock or polymicrobial sepsis. Signaling by TLRs may proceed through the adapter proteins MyD88 or TIR domain-containing adaptor inducinng IFN-β. Both pathways can lead to the production of type I IFNs (IFN-αβ). In the present study, the role of the type I IFN pathway for host defense and immune pathology in sepsis was investigated using a model of mixed bacterial peritonitis. Systemic levels of IFN-αβ protein were markedly elevated during septic peritonitis. More detailed analyses revealed production of IFN-β, but not IFN-α subtypes, and identified CD11b+CD11c- macrophage-like cells as major producers of IFN-/S. The results further demonstrate that in IFN-αβ receptor I chain (IFNARI)-deficient mice, the early recruitment of neutrophils to the infected peritoneal cavity was augmented, most likely due to an increased local production of MCP-1 and leukotriene B4. In the absence of IFNAMI, peritoneal neutrophils also exhibited enhanced production of reactive oxygen intermediates and elevated expression of Mac-1. Conversely, administration of recombinant IFN-β resulted in reduced leukotriene B4 levels and decreased peritoneal neutrophil recruitment and activation. Analysis of the cytokine response to septic peritonitis revealed that IFNARI-/- deficiency strongly attenuated late, but not early, hyperinflammation. In accordance with these findings, bacterial clearance and overall survival of IFNARI-/- mice were improved. Therefore, the present study reveals critical functions of the type I IFN pathway during severe mixed bacterial infections leading to sepsis. The results suggest that type I IFN exerts predominantly adverse efects under these conditions. Copyright © 2006 by The American Association of Immunologists, Inc.