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 3mg/kg for day 1 and day 14 experiments, respectively ; Bellon Laboratories). C57BL/6J 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.Le texte complet de cet article est disponible en PDF.
Keyword : Pathologies Interstitielles