Figure 5. Inhibition of the inflammasome/IL-1β pathway prevents the S. Typhimurium–induced cytokine storm in iron-loaded Fth^Δ/Δ mice.

Fth^Δ/Δ mice were i.v. administered iron isomaltoside (2 mg elementary Fe per animal) and infected 3 days later with 500 CFU GFP-expressing S. Typhimurium (STG). Mice were i.p. injected with the caspase-1 inhibitor Ac-YVAD-cmk (Casp1i, 8 mg/kg, 1 hour after infection, A–C) or the IL-1β receptor antagonist anakinra (25 mg/kg, 3 hours after infection, D–F). The treatment with Ac-YVAD-cmk or anakinra was repeated in 12-hour intervals. Control mice were administered PBS. (A) Surviving animal fractions as a function of time (n = 7 mice per group). (B) Serum levels of IL-1β, IL-6, and TNF-α measured by ELISA 20 hours after infection (Ctrl: n = 10, Casp1i: n = 7). (C) Bacterial burden of the spleen and liver determined by plating of organ lysates (Ctrl: n = 10, Casp1i: n = 7). (D) Surviving animal fractions as a function of time (n = 10 mice per group). (E) Serum levels of IL-1β, IL-6, and TNF-α measured by ELISA 20 hours after infection (n = 7 per group). (F) Bacterial burden of the spleen and liver was determined by plating of organ lysates 20 hours after infection (n = 7 per group). In A and D, data are presented as Kaplan-Meier plots. In other panels, each point denotes single animal, and bars with whiskers represent mean ± SEM. In A and D, statistical significance was assessed with Wilcoxon test. In the other panels, statistical significance was assessed with 2-tailed t test. In the plots, Wilcoxon and t test P value are indicated.