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.

Background-Th2 cells can further differentiate into dual positive Th2/Th17 cells. The presence of dual positive Th2/Th17 cells in the airways and its impact on asthma severity are unknown.

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.

Background The mechanism of Th2/Th17-predominant and Th2/Th17-low asthma is unknown. Objective To study the immune mechanism of Th2/Th17-predominant and Th2/Th17-low asthma. Methods In a previously reported cohort of 60 asthmatic patients, 16 patients were immunophenotyped with Th2/Th17-predominant asthma and 22 patients with Th2/Th17-low asthma. We examined BAL leukocytes, cytokines, mediators, and epithelial cell function for these asthma subgroups. Results Th2/Th17-predominant asthma had elevated IL1β, IL6, IL23, C3a and serum amyloid A (SAA) in BAL, and correlated with IL1β and C3a. Th2/Th17 cells expressed higher levels of the IL1 receptor and p-p38 MAPK. Anakinra, an IL1 receptor antagonist protein, inhibited BAL Th2/Th17 cells. Th2/Th17-low asthma had two distinct subgroups—neutrophilic asthma (45%) and pauci-inflammatory asthma (55%). This contrasted with Th2/Th17-predominant and Th2-predominant asthma, which had neutrophilic asthma in 6% and 0% of patients, respectively. BAL neutrophils strongly correlated with BAL myeloperoxidase, IL8, IL1α, IL6, G-CSF, and GM-CSF.. Sixty percent of the patients with neutrophilic asthma had a pathogenic microorganism in BAL culture, which suggested a subclinical infection. Conclusion We uncovered a critical role for the IL1β pathway in Th2/Th17-predminant asthma. A subgroup of Th2/Th17-low patients had neutrophilic asthma and elevated BAL IL1α, IL6, IL8, G-CSF, and GM-CSF. IL1α was directly involved in IL8 production and likely contributed to neutrophilic asthma. Sixty percent of neutrophilic patients had a subclinical infection.