IL‐37 alleviates house dust mite‐induced chronic allergic asthma by targeting TSLP through the NF‐κB and ERK1/2 signaling pathways

Interleukin (IL)‐37 has been described as a negative regulator of immune responses and is critical for asthma pathogenesis, but the mechanisms behind the protective role of IL‐37 against allergic asthma are less well understood. We show here that IL‐37 administered intranasally inhibited house dust mite (HDM)‐induced chronic airway eosinophilic inflammation, goblet cell hyperplasia, peribronchial collagen deposition and airway hyperresponsiveness (AHR) to methacholine. In contrast to a weakened Th2 response in the lung that was characterized by the downregulation of Th2‐associated cytokines and chemokines in IL‐37‐treated mice, IL‐37 has no effect on relevant markers of systemic Th2 immune including serum immunoglobulins expression and in vitro production of Th2‐associated cytokines by splenocytes on HDM recall. We demonstrated that the production of thymic stromal lymphopoietin (TSLP) in the lung tissue was associated with IL‐37. Importantly, compared with IL‐37 alone, TSLP coadministration with IL‐37 restored HDM‐induced airway inflammation and structural alterations, increased AHR to methacholine and promoted Th2‐associated cytokine production. We further found that IL‐37 inhibited the induction of TSLP expression by the main antigen of house dust mite, Der p1, by suppressing NF‐κB and extracellular signal regulated kinase 1/2 (ERK1/2) activation in human bronchial epithelial (16‐HBE) cells in vitro. These data highlight the importance of TSLP in IL‐37‐mediated protective role in asthma. IL‐37 might represent a useful innovative and alternative therapy to control TSLP production in the airway. Extracellular IL‐37 inhibits house dust mite (HDM)‐induced thymic stromal lymphopoietin (TSLP) production by suppressing the NF‐κB and ERK1/2 pathways in airway epithelial cells, which plays a critical role in protecting against allergen‐induced airway inflammation and structural remodeling. Therefore, IL‐37 presents a novel therapeutic target in chronic allergic asthma.