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

• 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

SummaryType 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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