Backgrounds: Exposure to air pollutant ozone leads to neutrophil infiltration in airway and severe airway hyperresponsiveness (AHR) in asthma models. However, the underlying mechanisms and possible therapeutic targets remain unclear.
Methods: In wild type (WT) mice and NLRP3 knockout mice, we used ovalbumin (OVA) sensitization/challenge to build a type 2-high asthma model, while OVA combined with ozone exposure (OVA+ozone) was used for the induction of asthma model with increased neutrophils. Spirometry and bronchial provocation tests in mice were carried out to evaluate the lung function and lung resistance of mice. HE staining, PAS staining and immunohistochemical analyses were undertaken to observe morphology changes in lungs. Cytokines in BALF of mice and in sputum supernatants of an asthma cohorts were measured by ELISA. NLRP3 in lung sections were determined by immunofluorescence.
Results: OVA and ozone induced NLRP3 expression in airway epithelial and macrophages of WT mice and neutrophil infiltration in airway, which were eliminated by NLRP3 knockout. Knockdown of NLRP3 reduced OVA and ozone induced AHR. NLRP3 knockout attenuated IL-1? production in lungs of OVA+ozone group. Both Th2 and Th17 related cytokines increased in OVA and ozone induced asthma model with neutrophil infiltration. IL-1? protein levels were increased together with NLRP3 inflammasome in sputum supernatants of the asthma cohorts.

Conclusions: NLRP3 inflammasome responses and its downstream cytokines drive AHR and neutrophil inflammation in experimental asthma model induced by OVA and ozone. IL-1? may be potential therapeutic targets in AHR of T2-low asthma.