Background Asthma in the mouse model spontaneously resolves after cessation of allergen exposure. We developed a mouse model where asthma features persisted for 6 months after cessation of allergen exposure. Objective To elucidate factors contributing to the persistence of asthma. Methods We utilized a combination of immunologic, genetic, microarray and pharmacologic approaches to dissect the mechanism of persistence of asthma. Results Elimination of T cells though antibody-mediated depletion or lethal irradiation and transplantation of Rag1−/− bone marrow in mice with chronic asthma resulted in resolution of airway inflammation but not airway hyperreactivity or remodeling. Elimination of T cells and ILC2 through lethal irradiation and transplantation of Rag2−/−γc−/− bone marrow or blockade of IL33 resulted in resolution of airway inflammation and hyperreactivity. Persistence of asthma required multiple interconnected feedback and feed forward circuits between ILC2 and epithelial cells. Epithelial IL33 induced ILC2, a rich source of IL13. The latter directly induced epithelial IL33 establishing a positive feedback circuit. IL33 auto-induced, generating another feedback circuit. IL13 upregulated IL33 receptors and facilitated IL33 auto-induction, thus establishing a feed forward circuit. Elimination of any component of these circuits resulted in resolution of chronic asthma. In agreement with the foregoing, IL33 and ILC2 were increased in the airways from asthmatic patients. IL33 correlated with disease severity. Conclusions We present a critical network of feedback and feed forward interactions between epithelial cells and ILC2 involved in maintaining chronic asthma. Although T cells contributed to the severity of chronic asthma they were redundant in maintaining airway hyperreactivity and remodeling.

No abstract

Dexamethasone inhibited type 2 cytokine production by blood ILC2s. IL-7 and TSLP abrogated this inhibition and induced steroid resistance of ILC2s in a MEK- and STAT5-dependent manner. BAL fluid ILC2s from asthmatic patients with increased TSLP levels were steroid resistant, which was reversed by clinically available inhibitors of MEK and STAT5.

The data suggest that severe asthmatics with persistent airway eosinophils manifest high levels of 15(S)-HETE in BALF, which may be associated with airway fibrosis. It is likely that 15-LO expression and activation by airway cells explain the increased 15(S)-HETE levels.