Critical Role of Signaling Through IL-1 Receptor for Development of Arthritis and Sepsis During Staphylococcus aureus Infection

Abstract

IL-1R-deficient mice (IL-1R−/−) and their wild-type controls (IL-1R+/+) were i.v. inoculated with 1 × 107 or 106 Staphylococcus aureus per mouse to mimic bacterial sepsis and septic arthritis. The disease outcome was severely worsened in the IL-1R−/− mice as compared with IL-1R+/+ mice. Indeed, 3 days after inoculation of 107 S. aureus per mouse 84% of IL-1R−/− mice displayed clinical signs of septicemia as compared with none of the IL-1R+/+ mice. On day 9 after inoculation with 106 S. aureus per mouse 75% of the IL-1R−/− mice were dead as compared with none of the IL-1R+/+ mice. Also, the number of staphylococci in circulation was 25- to 30-fold increased in IL-1R−/− mice as compared with IL-1R+/+ mice, the most probable reason for the outcome. The frequency and severity of septic arthritis were significantly increased in IL-1R−/− mice, as compared with IL-1R+/+ mice, following i.v. inoculation of staphylococci. This was probably due to an increased accumulation of bacteria in the joints of IL-1R−/− mice as compared with their wild-type controls. Interestingly, while serum levels of IL-18 in IL-1R−/− mice were significantly lower than in IL-1R+/+ mice 24 h after inoculation of S. aureus, both IL-18 and IL-1β were significantly increased in IL-1R−/− vs IL-1R+/+ mice 4 days after the bacterial inoculation. In conclusion, IL-1R signaling plays a crucial role in host protection during systemic S. aureus infection as seen by the fatal outcome of S. aureus sepsis and arthritis in IL-1R-deficient mice.