Macrophage STING signaling promotes fibrosis in benign airway stenosis via IL6-STAT3 axis

Abstract Benign airway stenosis (BAS) caused by tracheal intubation resuscitation measures is a difficult complication to ignore in the management of critically ill patients. However, the pathogenesis of this disease, which is characterized histologically by tracheal fibrosis, remains poorly understood. It has been shown that post-injury inflammatory processes play a key role in tissue fibrosis. However, we remain unclear about the relationship between inflammation induced by mechanical injury and BAS after tracheal intubation. Here, we found STING expression was increased in trachea after injury and inhibition or deletion of STING can alleviate tracheal fibrosis in BAS mice. Then, we reveal that released tracheal epithelial cell DNA resulting from mechanical injury activates macrophage STING. Further, macrophages with activated cGAS-STING pathway promote fibroblast fibrosis in the trachea via the IL6-STAT3 axis. We determined that the cGAS-STING pathway in macrophages is critical in causing tracheal fibrosis and ultimately benign airway stenosis. Our results provide a key cornerstone for future treatment of benign airway stenosis caused by mechanical injury.