STING/RANTES Pathway in Airway Epithelium Stimulates Sensitization to Der p1 in an Asthma Model

Abstract

BackgroundAsthma development can be attributed to various factors, including viral infections. Several pathogen including viruses activate stimulators of interferon genes (STING), and a small amount of STING agonist functions as adjuvants for sensitization to house dust mite (HDM); however, the associated mechanism is unclear. We investigated the role of STING during sensitization to HDM in airway epithelial cells. MethodsAirway epithelial cell STING expression was analyzed using the GEO database. We delivered cyclic-GMP-AMP (cGAMP), a STING agonist to mice intranasally, and sorted epithelial cells and performed RNA-seq. Human airway epithelial cells (HBEpCs) were stimulated using cGAMP in vitro. Next, we sensitized mice with cGAMP and HDM, Der p1 on Day 1, and challenged with HDM on Day 7, and on Day 8, analyzed cytokine/chemokine levels, bronchoalveolar lavage cell fraction, histology, and the number of group 2 innate lymphoid cells (ILC2s) and dendritic cells (DCs). Furthermore, we evaluated the effect of RANTES/CCL5 alone on sensitizing to HDM. ResultsRelative to other pattern recognition receptors, TMEM173, encoding STING, was highly expressed in HBEpCs, and RANTES expression was remarkably upregulated in cGAMP-treated mice. RANTES, not IL-33 or TSLP, was also activated by cGAMP in HBEpCs, especially in the presence of H2O2. Type 2 cytokine/chemokine, eosinophil, and goblet cell metaplasia increased with ILC2 and cDC2 accumulation in cGAMP-adjuvanted HDM-sensitized mice. RANTES alone functioned as an adjuvant for induction of type 2 inflammation in mice. ConclusionSTING was highly expressed in airway epithelial cells. STING/RANTES axis may be a crucial pathway for stimulating asthma sensitization.