Work

Inhibiting DNA Sensing Pathway Controls Steroid Hyporesponsive Lung Inflammation

Year: 2024

Type: article

Abstract: DNA damage underlies the progression of asthma toward a severe, steroid hyporesponsive phenotype. The accumulation of double-stranded DNA within the cytosol triggers the activation of cytosolic DNA-sensing pathways, notably the Stimulator of Interferon Genes (STING) pathway. However, the precise role of STING in driving steroid hyporesponsiveness remains elusive and warrants further investigation. This study evaluates STING levels in human bronchial fibroblasts from severe asthmatic patients and in lung homogenates from a steroid hyporesponsive lung inflammation mouse model. STING level is assessed at baseline, post house dust mites (HDM) stimulation, and following treatment with dexamethasone and STING inhibitor. The effect of STING inhibitors on regulating steroid hyporesponsiveness particularly glucocorticoid receptor (GR)-α/GR-β ratio is also examined. Severe asthmatic fibroblasts exhibit elevated STING/IFN-I pathway activation, further heightened by HDM and a similar pattern is seen in lung homogenates from steroid hyporesponsive mice. Dexamethasone combined with an STING inhibitor reduces STING activity, while dexamethasone alone is ineffective. Interestingly, the STING inhibitor restores steroid sensitivity by increasing the GRα/GRβ ratio. Furthermore, nanoparticle-encapsulated STING inhibitor more effectively reduces airway hyperresponsiveness and restores steroid sensitivity than the free inhibitor. These findings emphasize STING's role in severe asthma pathogenesis, proposing nanoparticle delivery of STING inhibitors as a promising therapeutic strategy.

Source: Advanced Biology

DOI: 10.1002/adbi.202400230