Stimulation of innate immune response induces long term allergic sensitization and allergic airway inflammation independent of STAT-6

Abstract

Rationale According to the current paradigm, the transcription factor STAT6 is required for induction of allergic sensitization and allergic airway inflammation. Recent studies have shown that stimulation of innate immune responses profoundly modulate many immune responses. The conserved MyD88 signaling pathway of innate immune response can be stimulated by the cytokine IL-18. We have reported that intrapulmonary administration of IL-18 with ragweed pollen extract (RWE) induces allergic sensitization and allergic inflammation in wild type mice. Here we examined role of IL-18 on long-term induction of allergic sensitization in mice lacking STAT-6. Methods To examine the long-term effects of intrapulmonary administration of IL-18, wild type and STAT6 knockout mice received intranasally either RWE or RWE+IL-18. 12 weeks later, all mice were challenged with RWE. 72 hours later a BAL was performed. BUXCO plethysmography was used to monitor AHR. Antigen recalls studies were performed using splenocytes. Serum RWE-specific IgE ELISA also quantified. Statistical significance was set at p<0.05. Results Compared to the mice sensitized with RWE, RWE challenge of both wild type and STAT6 deficient mice sensitized with RWE+IL-18 induced 5-fold higher recruitment of eosinophils (p<0.01), 11-fold higher serum IgE levels (p<0.0001), 2-fold higher airway hyperesponsiveness (p<0.05) and 10- to 25-fold higher splenocytes Th2 memory responses (<0.001). Conclusions Stimulation of the innate immune response by intrapulmonary administration of IL-18 induces long lasting (12 weeks) allergic sensitization, AHR, allergic airway inflammation and Th2 memory via a novel STAT-6 independent pathway.