STING pathway contributes to Steroid-Hyporesponsive Lung Inflammation in DSS-induced colitis mice model.

Abstract

BACKGROUND: Inflammatory bowel disease (IBD), a chronic inflammation of the gastrointestinal tract, is well recognized for triggering extraintestinal manifestations, including pulmonary complications. Emerging evidence highlights the gut lung axis (GLA) as a critical link in respiratory health, where gut dysbiosis and bacterial translocation play a role in systemic and pulmonary inflammation. Despite its clinical relevance, the mechanisms underlying these pulmonary manifestations remain poorly understood. The Stimulator of Interferon Genes (STING) pathway plays a critical role in regulating pulmonary inflammation. However, its precise role in colitis-associated lung inflammation remains unclear and could provide novel insights into the pathogenesis of this condition. METHODS: This study evaluates the involvement of STING pathway in colitis induced lung tissue inflammation using a dextran sulfate sodium (DSS) murine model of colitis. The effect of STING inhibitor on regulating steroid hypo-responsiveness, particularly the glucocorticoid receptor GR-α/GR-β ratio, is also examined. RESULTS: The DSS model induces lung inflammation, characterized by enhanced infiltration of inflammatory cells into lung tissues, increased levels of IL-17, IFN-γ, bacterial DNA, while enhancing steroid hypo-responsiveness. The inhibition of STING controls lung inflammation and restores steroid sensitivity to a much higher extent compared to dexamethasone treatment. CONCLUSION: The significant activation of the STING pathway and dysregulation of steroid signature markers in the lungs of DSS-induced colitis mice suggest a novel mechanism by which gut inflammation may propagate to the lungs.