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Type I IFN Modulates Host Defense and Late Hyperinflammation in Septic Peritonitis¹

Heike Weighardt^2,*, Simone Kaiser-Moore^*, Sylvia Schlautkötter^*, Tanja Rossmann-Bloeck^*, Ulrike Schleicher, Christian Bogdan and Bernhard Holzmann^*

^* Department of Surgery, Technische Universität München, Munich, Germany; and Department of Microbiology and Hygiene, Institute of Medical Microbiology and Hygiene, University Clinic of Freiburg, Freiburg, Germany

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-. Both pathways can lead to the production of type I IFNs (IFN-). 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- protein were markedly elevated during septic peritonitis. More detailed analyses revealed production of IFN-, but not IFN- subtypes, and identified CD11b⁺CD11c^– macrophage-like cells as major producers of IFN-. The results further demonstrate that in IFN- 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 IFNARI, peritoneal neutrophils also exhibited enhanced production of reactive oxygen intermediates and elevated expression of Mac-1. Conversely, administration of recombinant IFN- 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 effects under these conditions.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Deutsche Forschungsgemeinschaft Grants (SFB 576 Project A7 to B.H. and H.W.) and SFB 620 Project A9; DFG Bo996/3-2 and 3-3 (to U.S. and C.B.) and by the Kommission für Klinische Forschung, Klinikum rechts der Isar.

² Address correspondence and reprint requests to Dr. Heike Weighardt, Department of Surgery, Technische Universität München, Ismaninger Strasse 22, 81675 Munich, Germany. E-mail address: weighardt{at}chir.med.tu-muenchen.de

³ Abbreviations used in this paper: TRIF, TIR domain-containing adaptor inducing IFN-; CASP, colon ascendens stent peritonitis; IFNAR, IFN- receptor; IP10, IFN--inducible protein 10; VSV, vesicular stomatitis virus; LTB₄, leukotriene B₄.

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