IL1RAP is an emerging target in chronic airway inflammatory diseases

Background: Airway diseases like asthma and COPD are associated with chronic inflammation. Multiple mediators/pathways can be dysregulated which then drives disease pathogenesis. IL-1 family members (IL-1α, IL-1β, IL-33, IL-36) have been linked to asthma and COPD, thus targeting them in combination could lead to a disease modifying therapy. IL1RAP is the common co-receptor involved in the signaling of IL-1, IL-33 and IL-36 (via IL-1R, ST2R and IL-36R) and therefore represents an exciting target. Aim and objective: The aim of this work was to determine the role of IL1RAP in murine lung by using genetically modified mice (IL1RAP KOs) and airway inflammatory models where the IL-1 family receptors play central roles. Methodology and principle findings: We compared the airway inflammation in wild type (WT) and IL1RAP KO mice after exposure to cigarette smoke (known to be dependent on the IL-1R) or IL-33 instillation (dependent on the ST2R). Cigarette smoke exposure caused an increase in BALF inflammatory cytokines and neutrophilia as well as mucin production in the lungs of the WT mice, whereas in the IL1RAP KO mice this inflammation was almost completely absent. Similarly, after IL-33 challenge, the WT mice had a robust increase in BALF IL-5 and eosinophilia but in the IL1RAP KO mice, the levels were similar to the unchallenged mice. Conclusion: Our data provide evidence for a central role for IL1RAP in airway inflammation driven by IL-1 and IL-33, and encourages further research to explore beneficial aspects of blocking IL1RAP coreceptor in chronic respiratory diseases.