Thymic stromal lymphopoietin contributes to ozone-induced airway
responses via conventional type 1 dendritic cells in mice
Abstract
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.