Distal airways are protected from goblet cell metaplasia by diminished expression of IL-13 signalling components.

BACKGROUND: Increased mucus production is a critical factor impairing lung function in patients suffering from bronchial asthma, the most common chronic inflammatory lung disease worldwide. OBJECTIVE: This study aimed at investigating whether goblet cell (GC) metaplasia and mucus production are differentially regulated in proximal and distal airways. METHODS: Female Balb/c mice were sensitized to ovalbumin (OVA) and challenged with an OVA-aerosol on two consecutive days for 1 week (acute) or 12 weeks (chronic). Real-time RT-PCR analysis was applied on microdissected airways. RESULTS: In acutely and chronically OVA-challenged mice, GC metaplasia and mucus production were observed in proximal but not in distal airways. In contrast, inflammation reflected by the infiltration of eosinophils and expression of the TH2-type cytokines IL-4 and IL-13 was increased in both proximal and distal airways. Abundance of IL-13Rα1 was lower in distal airways of healthy control mice. Under acute and chronic OVA-exposure, activation of IL-13Rα1-dependent signalling cascade, reflected by Spdef and Foxo3A transcription factors, was attenuated in distal compared to proximal airways. CONCLUSION AND CLINICAL RELEVANCE: These data indicate that distal airways might be less sensitive to IL-13-induced GC metaplasia and mucus production through lower expression of IL-13Rα1 and attenuated activation of downstream signalling. This might represent a protective strategy to prevent mucus plugging of distal airways and thus impaired ventilation of attached alveoli.

IL-37 requires IL-18Rα and SIGIRR/IL-1R8 to diminish allergic airway inflammation in mice.

BACKGROUND: Interleukin (IL) 37 has been described as a negative regulator of innate immunity, as it reduces the activation and cytokine production of different innate immune cells. Recently, results from the CLARA childhood asthma cohort suggested an implication of IL-37 for human asthma pathogenesis. This study aimed to investigate the effects of IL-37 on allergic airway inflammation in a mouse model of experimental asthma. METHODS: Peripheral blood mononuclear cells (PBMCs) of children were cultured for 48 h (anti-CD3/anti-CD28 stimulation or unstimulated), and IL-37 concentrations in supernatants were determined. Wild-type, IL-18Rα-deficient ((-/-) ), and SIGIRR(-/-) C57BL/6 mice were sensitized to ovalbumin (OVA) and challenged with OVA aerosol to induce acute experimental asthma, and IL-37 was applied intranasally prior to each OVA challenge. Airway hyper-responsiveness (AHR), airway inflammation, cytokine levels in broncho-alveolar lavage fluid, and mucus production were determined. RESULTS: IL-37 production of human PBMCs was significantly lower in allergic asthmatics vs healthy children. In wild-type mice, intranasal administration of IL-37 ablated allergic airway inflammation as well as cytokine production and subsequently diminished the hallmarks of experimental asthma including mucus hyperproduction and AHR. In contrast, local application of IL-37 produced none of these effects in mice lacking either IL18Rα or SIGIRR/IL-1R8. CONCLUSIONS: This study demonstrates that IL-37 is able to ablate a TH2 cell-directed allergic inflammatory response and the hallmarks of experimental asthma in mice, suggesting that IL-37 may be critical for asthma pathogenesis. Furthermore, these data suggest a mode of action of IL-37 that involves IL18Rα as well as the orphan receptor SIGIRR/IL-1R8.