Interleukin-1 receptor and caspase-1 are required for the Th17 response in nitrogen dioxide-promoted allergic airway disease

Nitrogen dioxide (NO₂) is an environmental pollutant and endogenously generated oxidant associated with the development, severity,andexacerbationofasthma.NO₂ exposure is capableofallergically sensitizing mice to the innocuous inhaled antigen ovalbumin (OVA),promotingneutrophilandeosinophil recruitment,andamixed Th2/Th17 response upon antigen challenge that is reminiscent of severeasthma. However, the identityof IL-17A-producingcells and the mechanisms governing their ontogeny in NO₂-promoted allergic airway disease remain unstudied. We measured the kinetics of lunginflammation after antigen challenge inNO ₂-promoted allergic airway disease, including inflammatory cells in bronchoalveolar lavage and antigen-specific IL-17A production from the lung. We determined that IL-17A⁺ cells were predominately CD4⁺T cell receptor (TCR)β⁺ Th17 cells, and that a functional IL-1 receptor was required for Th17, but not Th2, cytokine production after in vitro antigen restimulation of lung cells. The absence of natural killer T cells, γδ T cells, or the inflammasome scaffold nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain (Nlrp)3 did not affect the development of NO₂-promoted allergic inflammation or IL-17A production. Similarly, neutrophil depletion or the neutralization of IL-1α during sensitization exerted no effect on these parameters. However, the absence of caspase-1 significantly reduced IL-17A production from lung cells without affecting Th2 cytokines or lung inflammation. Finally, the intranasal administration of IL-1β and the inhalation of antigen promoted allergic sensitization that was reflected by neutrophilic airway inflammation and IL-17A production from CD4⁺TCRβ⁺ Th17 cells subsequent to antigen challenge. Thesedataimplicatearolefor caspase-1andIL- 1βintheIL-1receptor- dependent Th17 response manifest in NO ₂-promoted allergic airway disease.