Idiopathic pulmonary fibrosis (IPF) is the most common chronic and progressive Interstitial Lung Diseases (ILD) with fatal ending. Immunological processes involved remain poorly understood. STING (Stimulator of interferon genes), encoded by Tmem173 gene, is an innate immune sensor activated by cyclic dinucleotides upon sensing of cytoplasmic host or foreign DNA leading to type I/III interferons (IFN) production as well as cell death and autophagy regulations. STING has been described as a critical player in several inflammatory and autoimmune diseases. We recently showed that STING displays a protective role using the mouse model of bleomycin (BLM)-induced lung fibrosis, independently of type I IFN signaling. We now aim to characterize STING-mediated mechanisms that trigger protection and assess whether stimulation of the STING pathway may elicit beneficial outcome.

We used the classical model of IPF by oropharyngeal administration of BLM (2mg/kg, Bellon Laboratories). C57BL/6J wild type (WT) adult (8–14-week old) males were used, together with mice deficient for STING (Sting-/-) and type I interferon (IFN) receptor (Ifnar1-/-). WT mice were treated with the autophagy inducer Carbamazepin (80mg/kg) or di-amidobenzimidazole (DiABZI, 0.05mg/kg) as a potent STING agonist.

Our first results show that lung expression of autophagy related proteins ATG5, P62 and LC3B-II is reduced in BLM-treated Sting-/- mice in comparison to their WT relatives indicating that BLM-induced autophagy depends on STING. Carbamazepin treatment led to a significant decrease of recruited CD45+ immune cells in the lungs, together with reduced TIMP1/MMP9 remodeling factor expressions and collagen deposition. These results may indicate that STING elicits anti-fibrotic function through autophagy upregulation. We also generated data suggesting that STING stimulation induced by DiABZI administration attenuates BLM-induced lung fibrosis.

Together, our data may support an unprecedented immunoregulatory function of STING in lung fibrosis through the induction of autophagy. We are currently performing experiments to validate our hypotheses.