Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33

Abstract

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.

Secreted PLA2 group X orchestrates innate and adaptive immune responses to inhaled allergen

“…We found a marked reduction in the generation of CysLTs and PGD 2 in the airways of Pla2g10-deficient mice, which is particularly important as both IL-33 and the proximal CysLTs LTC 4 and LTD 4 provide important and nonredundant signals for ILC2 activation (51). These findings indicate that sPLA 2 -X serves as a central regulator of ILC2s in the lung, a finding that has substantial clinical relevance, given the recent evidence that ILC2s play an active role in the lungs of asthmatics (52)(53)(54)(55)(56).…”

DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma

“…First, DUOX1 critically contributes to EGFR activation in response to external damaging stimuli, including allergens, by promoting epithelial IL-33 secretion and subsequent activation type 2 cytokine responses (IL-5, IL-13) in ILC2s, for example, as well as other lung cell types (14). In turn, IL-13 is capable of enhancing epithelial EGFR activation and inducing epithelial expression of DUOX1 (45) as well as IL-33 and its receptor (IL33R, also known as ST2) (46), thus generating positive feedback loops that result in amplified and prolonged epithelial responses to allergen challenge. An additional consequence of IL-33-mediated ILC2 recruitment and activation is the production of AREG, which forms an essential component of EGFR-mediated epithelial repair responses in the context of parasite/helminth infection (47) but may also contribute to sustained EGFR activation in chronic asthma.…”

Novel concepts in airway inflammation and remodelling in asthma

“…This means complex models need to be developed. An example is the recent development of a mouse model in which features of allergic airways disease persisted for up to 6 months after allergen exposure had ceased [78]. Not only can this be used to study factors underlying disease remission, but also to understand disease persistence.…”

“…The complexity of factors causing disease persistence was demonstrated in this chronic model as three comparator allergen exposures (ragweed, Alternaria and HDM) and knockout of two separate lymphoid cell types (T-cells and innate lymphoid cells) were used. Multiple feedback and feed-forward circuits between innate lymphoid cells, epithelial cells, IL-33 and IL-13 were identified, but the key clinical message was the importance of IL-33 in maintaining disease, not in inception [78]. A similar message arose from translational work using a neonatal mouse model and airway samples from children with severe therapy-resistant asthma.…”