Type I Interferon Signaling Prevents IL-1β-Driven Lethal Systemic Hyperinflammation during Invasive Bacterial Infection of Soft Tissue

• Published in: Cell host & microbe Vol. 19; no. 3; pp. 375 - 387
• Main Authors: Castiglia, Virginia, Piersigilli, Alessandra, Ebner, Florian, Janos, Marton, Goldmann, Oliver, Damböck, Ursula, Kröger, Andrea, Weiss, Sigfried, Knapp, Sylvia, Jamieson, Amanda M., Kirschning, Carsten, Kalinke, Ulrich, Strobl, Birgit, Müller, Mathias, Stoiber, Dagmar, Lienenklaus, Stefan, Kovarik, Pavel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09-03-2016
• Subjects: Animals; Disease Models, Animal; Interferon Type I - metabolism; Interleukin-1beta - metabolism; Mice; Mice, Knockout; Signal Transduction; Soft Tissue Infections - immunology; Soft Tissue Infections - pathology; Streptococcal Infections - immunology; Streptococcal Infections - pathology; Survival Analysis
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2016.02.003

Type I interferons (IFN-Is) are fundamental for antiviral immunity, but their role in bacterial infections is contradictory and incompletely described. Streptococcus pyogenes activates IFN-I production in innate immune cells, and IFN-I receptor 1 (Ifnar1)-deficient mice are highly susceptible to S. pyogenes infection. Here we report that IFN-I signaling protects the host against invasive S. pyogenes infection by restricting inflammation-driven damage in distant tissues. Lethality following infection in Ifnar1-deficient mice is caused by systemically exacerbated levels of the proinflammatory cytokine IL-1β. Critical cellular effectors of IFN-I in vivo are LysM+ and CD11c+ myeloid cells, which exhibit suppression of Il1b transcription upon Ifnar1 engagement. These cells are also the major source of IFN-β, which is significantly induced by S. pyogenes 23S rRNA in an Irf5-dependent manner. Our study establishes IL-1β and IFN-I levels as key homeostatic variables of protective, yet tuned, immune responses against severe invasive bacterial infection.
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•LysM+ and CD11c+ myeloid cells are major sources of IFN-I in S. pyogenes-infected mice•S. pyogenes-infected Ifnar1−/− mice display hyperinflammation and tissue damage•Systemic levels of IL-1β are increased in S. pyogenes-infected Ifnar1−/− mice•IFN-I is required to control IL-1β levels and ensure a balanced inflammatory response
Successful host defense requires precisely balanced immune responses to ensure pathogen clearance while limiting exaggerated inflammation and tissue destruction. Castiglia et al. report that activation of type I interferon signaling in the context of Streptococcus pyogenes infection controls IL-1β levels and limits systemic inflammation and tissue damage.