Crucial role of stimulator of interferon genes‐dependent signaling in house dust mite extract‐induced IgE production (1)
Stimulator of interferon genes (STING) is a transmembrane protein localized in the endoplasmic reticulum. The pathway is initiated when exogenous DNA, such as viral and bacterial DNA, binds to cyclic GMP-AMP synthase (cGAS) in the cytoplasm. Activated cGAS synthesizes cyclic GMP-AMP (cGAMP) as a second messenger from GTP and ATP. House dust extract mite (HDM), major cause of allergic asthma, activate signaling through Toll-like receptor (TLR) 4 and TLR2 and is involved in asthmatic inflammation. In addition to the fact that group 2 mite allergens have functional homology with a critical molecule (myeloid differential factor 2) in the signal transduction of TLR4, group 2 mite allergens can stimulate epithelial cells through TLR2.
In female B6 WT and Sting/− mice intratracheally administered HDM extract, total cell, eosinophil, and neutrophil numbers in BALF were higher in the HDM group than in the saline group. In the HDM group, both total IgE and HDM-specific IgE production significantly decreased in Sting−/− mice compared with WT mice.
The percentage of B cells (B220+) in BALF significantly decreased in Sting−/− mice compared with WT mice, whereas that of T cells (CD3+) did not decrease. The percentage of IgE-positive B cells (B220+, IgE+) was significantly lower in Sting−/− mice than WT mice.
WT mice were administered cGAMP and HDM extract intratracheally. The number of total cells in BALF increased in the cGAMP + HDM group compared with the HDM alone group. The proportion of B cells in BALF increased in the cGAMP + HDM group compared with the HDM alone group. Total and HDM-specific IgE levels increased the cGAMP + HDM group compared with the HDM alone group.
No differences in the IL-4 and IL-13 levels between WT and Sting−/− mice were observed. The levels of IL-4 and IL-13 in the culture supernatant and found that these levels were decreased in Sting−/− mice compared with WT mice.
The number of Tfh cells in the MLNs was found to be significantly lower in Sting−/− mice than WT mice. IL-4 expression in Tfh cells was not found to differ between WT and Sting−/− mice .
STING may affect Tfh cells and the class-switch recombination of B cells, resulting in defective IgE production. DNA damage at the site of allergic inflammation, and accumulation of cytosolic dsDNA in airway epithelium treated by allergens resulting in activating STING to promote inflammation.