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Protective role of the nucleic acid sensor STING in idiopathic pulmonary fibrosis - 09/03/22

Doi : 10.1016/j.rmr.2022.02.044 
F. Savigny, S. Carignon, N. Lacerda-Queiroz, S. Huot-Marchand, E. Kaya, B. Ryffel, A. Gombault, M. Le Bert, I. Couillin, N. Riteau
 Experimental and Molecular Immunology and Neurogenetics Laboratory (INEM), CNRS UMR7355 and University of Orleans, Orleans, France 

Corresponding author.

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Résumé

Introduction

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.

Methods

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-/−).

Results

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.

Conclusion

Together, our data support an unprecedented immunoregulatory function of STING in lung fibrosis that may rely on STING-dependent IL-28 and/or autophagy.

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Keyword : Pathologies Interstitielles


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© 2022  Publié par Elsevier Masson SAS.
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Vol 39 - N° 2

P. 127 - février 2022 Retour au numéro
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