IL-33 AND TSLP MEDIATE STEROID-RESISTANT AIRWAY INFLAMMATION IN MICE

Steroid-insensitive asthma is most often described as a chronic inflammatory disease that presents airway constriction and recurrent exacerbations even when treated with steroid-based therapies. Thus far, pulmonary preclinical models have focused on steroid sensitive, Th₂driven, allergic inflammation. Here we describe a pulmonary mouse model that utilizes IL-33 and TSLP with steroid insensitive eosinophilic features.

                IL-33 plays a critical role in various inflammatory and immunological pathologies. Intra-nasal administration of IL-33 to wild-type and Rag2-/- mice creates an influx of inflammatory cells and cytokines to the airway. Dexamethasone treatment was effective at reducing the recruitment of eosinophils to the airway and suppressing IL-5 and IL-13 producing lung resident Innate Lymphoid cells type 2 (ILC2). Conversely, Dexamethasone was ineffective at modulating ILC2 and eosinophil recruitment into the airway once IL-33 plus TSLP administrated intra-nasally. In addition, multiple Th2 cytokines in the bronchoalveolar lavage fluid and lung homogenate were protected, potentially driving steroid “insensitivity.”

                The IL33/TSLP mouse model has several steroid insensitive endpoints and could be a useful model for dissecting pathways and mechanism mediating steroid resistant eosinophilic lung inflammation.