Protective role of the nucleic acid sensor STING in idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is the most common type of interstitial lung disease, characterized by progressive lung scarring and a high mortality rate. IPF has no cure and available treatments at best delay disease progression. IPF is largely driven by host-derived danger signals released upon recurrent local tissue damage. We explore the roles of self-DNA and the intracellular DNA sensor stimulator interferon genes (STING), which activation leads to type I/III interferons (IFN) production and autophagy induction. We used the classical model of IPF by intranasal administration of bleomcyin (BLM) (7.5 and 3 mg/kg for day 1 and day 14 experiments, respectively ; Bellon Laboratories). C57BL/6 J wild type (WT) adult (8–14-week old) males were used, together with mice deficient for STING (Sting -/− ), cGas -/− and type I interferon (IFN) receptor (Ifnar1 -/− ). We report that STING deficiency leads to exacerbated pulmonary fibrosis with increased lung collagen deposition and excessive remodeling factors expression. We show that STING-mediated protection does not rely on type I IFN signaling nor IL-17A or TGF-β modulation. Interestingly, we observed persistent airway neutrophilia and decreased type III IFN (IL-28) in lung tissues of BLM-treated Sting -/− mice in comparison to their WT counterparts. We hypothesize that STING may limit neutrophilic inflammation through IL-28 signaling, downregulating subsequent adaptive immunity, remodeling and fibrosis. In addition, STING displays important anti-inflammatory properties through its phylogenetically conserved autophagy-inducing pathway. Autophagy favors collagen degradation and mouse survival in experimental lung fibrosis and autophagy-related proteins are decreased in IPF patients. Interestingly, 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. Together, our data support an unprecedented immunoregulatory function of STING in lung fibrosis that may rely on STING-dependent IL-28 and/or autophagy.