Interleukin-33 Induces a Protective Response Against Irritant-induced Airway Inflammation and Dysfunction.

Interleukin-33 (IL-33) released by injurious stimuli to airway epithelium activates innate lymphoid cells (ILCs) that express IL-13. IL-33 and ILCs have an important role in T2-high asthma but their influence on airway dysfunction induced by irritants is unclear. We examined the effects of Cl₂ inhalation on IL-33 release, pulmonary ILCs, airway inflammation and airway hyperresponsiveness (AHR). Cl₂ exposure resulted in IL-33 release and increased ILC2s in the airways of BALB/c mice. Inhibition of the IL-33 receptor did not alter AHR but depletion of ILCs augmented AHR. Recombinant IL-33 given for 3 successive days to wild type and recombinant activating gene deficient (Rag1^-/-) mice, deficient in mature T and B cells, further increased ILC2s and inhibited Cl₂ induced neutrophilia and AHR, whereas Rag^-/- IL2rγ^-/- mice, lacking ILCs, did not show these effects. IL-33 increased IL-13 expression by ILC2s, and IL-13 neutralization exacerbated AHR, whereas IL-13 administration reduced AHR in Cl₂-exposed Rag1^-/- mice. Il-33 biased alveolar macrophages towards the M2 phenotype, partly mediated by IL-13. Depletion with clodronate liposomes abrogated the IL-33 protective effect on AHR. The data suggest that the expansion of ILC2s by IL-33 activates a protective pathway involving IL-13 and macrophages against airway dysfunction and inflammation following inhalation of Cl₂.