Abstract
Idiopathic pulmonary fibrosis (IPF) is the most common and severe type of interstitial lung disease for which current treatments display limited efficacy. IPF is largely driven by host-derived danger signals released upon recurrent local tissue damage. Here we explored the roles of self-DNA and stimulator of interferon genes (STING), a protein belonging to an intracellular DNA sensing pathway that leads to type I and/or type III interferon (IFN) production upon activation. Using a mouse model of IPF, we report that STING deficiency leads to exacerbated pulmonary fibrosis with increased collagen deposition in the lungs and excessive remodeling factors expression. We further show that STING-mediated protection does not rely on type I IFN signaling nor on IL-17A or TGF-β modulation but is associated with dysregulated neutrophils. Together, our data support an unprecedented immunoregulatory function of STING in lung fibrosis.
Highlights
Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia [1, 2], characterized by progressive lung scarring causing shorter life expectancy and high mortality rate [2, 3]
As compared to saline (NaCl) control wild-type (WT) mice, we noted that double-stranded DNA (dsDNA) content is significantly increased in the bronchoalveolar lavage fluid (BALF) of BLM-treated Wild-type C57BL/6J (WT) mice (Figure 1A) and BLM treatment leads to a strong increase of cyclic GMP-AMP synthase (cGAS) (Mb21d1) (Figure 1B) and stimulator of interferon genes (STING) (Tmem173) (Figure 1C) gene expressions in the lungs
We assessed cGAS and STING protein expressions in saline- or BLM-treated WT mice, cGAS (Cgas-/-) or STING (Sting-/-) deficient mice. Both cGAS and STING protein expressions are increased in the lungs of BLM-treated WT mice and cGAS or STING levels are not impaired by the absence of STING or cGAS, respectively (Figures 1D, E)
Summary
Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia [1, 2], characterized by progressive lung scarring causing shorter life expectancy and high mortality rate [2, 3]. While the etiology is still unclear, it is believed that the physiopathology relies on repeated local micro-injuries triggering DNA damage, unbalanced cell death and aberrant tissue remodeling with extracellular matrix components and fibrosis [1,2,3,4]. Immune cells such as macrophages, neutrophils and T helper 17 (Th17) cells recruited to the lung tissue are known to display important proinflammatory and profibrotic functions [5].
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