Hiroki Tashiro

and 11 more

Background: Ozone as an external stimulant is considered to induce airway hyperresponsiveness (AHR) and neutrophilic airway inflammation, a particular phenotype of asthma. Recently, epithelial cell-derived cytokines such as thymic stromal lymphopoietin (TSLP) have been recognized as therapeutic targets for asthma with type 2 low inflammation, but the mechanisms remain unknown. Methods: Wild type (WT) mice and TSLP receptor-deficient mice were exposed to ozone at 2 ppm for 3 hours. AHR, cell counts, and cytokine and chemokine analyses of bronchoalveolar lavage fluid (BALF) were examined. Single-cell RNA sequencing analyses were performed to explore targeted cell clusters and genes. Batf3-deficient mice were analyzed to assess the effects of conventional type 1 dendritic cells (cDC1s), and treatment with NP-G2-044 was given to evaluate the impact of fascin on ozone-induced airway responses. Results: Ozone augmented AHR and increased neutrophils in BALF and TSLP in lungs with airway epithelial cell injury. Blockade of TSLP signaling attenuated ozone-induced AHR and increased neutrophil counts in BALF. Single-cell RNA sequencing showed that DCs, especially cDC1s, were affected by ozone exposure and blockade of TSLP in terms of gene expressions including Fscn1. Batf3-deficient mice showed attenuation of ozone-induced AHR and increased neutrophils in BALF with depletion of cDC1s. TSLP directly induced fscn1 from bone marrow-derived cDC1s, and NP-G2-044, an inhibitor of fascin, attenuated ozone-induced elevation of neutrophils in BALF. Conclusions: TSLP is crucial for ozone-induced AHR and neutrophilic airway inflammation via cDC1s. As the mechanism, fascin derived from cDC1 is associated with neutrophilic airway inflammation.