Abstract
Senescence and mitochondrial stress are mutually reinforcing age-related processes that contribute to idiopathic pulmonary fibrosis (IPF); a lethal disease that manifests primarily in the elderly. Whilst evidence is accumulating that GMP-AMP synthase (cGAS) is crucial in perpetuating senescence by binding damaged DNA released into the cytosol, its role in IPF is not known. The present study examines the contributions of cGAS and self DNA to the senescence of lung fibroblasts from IPF patients (IPF-LFs) and age-matched controls (Ctrl-LFs). cGAS immunoreactivity was observed in regions of fibrosis associated with fibroblasts in lung tissue of IPF patients. Pharmacological inhibition of cGAS or its knockdown by silencing RNA (siRNA) diminished the escalation of IPF-LF senescence in culture over 7 days as measured by decreased p21 and p16 expression, histone 2AXγ phosphorylation and/or IL-6 production (P < 0.05, n = 5-8). The targeting of cGAS also attenuated etoposide-induced senescence in Ctrl-LFs (P < 0.05, n = 5-8). Levels of mitochondrial DNA (mDNA) detected by qPCR in the cytosol and medium of IPF-LFs or senescence-induced Ctrl-LFs were higher than Ctrl-LFs at baseline (P < 0.05, n = 5-7). The addition of DNAse I (100 U/ml) deaccelerated IPF-LF senescence (P < 0.05, n = 5), whereas ectopic mDNA or the induction of endogenous mDNA release augmented Ctrl-LF senescence in a cGAS-dependent manner (P < 0.05, n = 5). In conclusion, we provide evidence that cGAS reinforces lung fibroblast senescence involving damaged self DNA. The targeting of cGAS to supress senescent-like responses may have potential important therapeutic implications in the treatment of IPF.
Highlights
idiopathic pulmonary fibrosis (IPF) is a lethal lung disease that increases in incidence with advancing age; characterised by an excessive fibrosis that impedes gas exchange [1]
CGAS expression is increased in IPF IHC shows cGAS antigen is associated with flattened elongate mesenchymal cells, comprising fibroblasts and smooth muscle cells, as well as cuboidal epithelial cells in the fibrotic lung of three IPF patients in vivo (Fig. 1). cGAS detection in lung section from two additional IPF patients are presented in the online supplement (Fig. S1). cGAS antigen was sparsely detected in the structural cells of lung tissue from control donors, which are mainly alveolar epithelial cells (Fig. 1 & Fig. S1)
Targeting cGAS diminishes the escalation of IPF-lung fibroblasts (LFs) senescence Inhibiting cGAS in IPF-LFs with RU.521 (3 M) diminished the escalation of replicative senescence in culture
Summary
IPF is a lethal lung disease that increases in incidence with advancing age; characterised by an excessive fibrosis that impedes gas exchange [1]. The pharmacological therapies currently used to treat IPF at best slow disease progression in some patients, do not reverse fibrosis, are expensive and have significant side-effects [3, 4]. Due to the slow onset and nature of symptoms, the fibrosis at the time of diagnosis is firmly entrenched and self-perpetuating and as such, the most feasible approach to treating IPF is to target the triggers of the ongoing fibrosis. Recent studies show that premature senescence in alveolar epithelial cells (AECs) and lung fibroblasts (LFs) underlie key pathological changes in IPF such as a highly activated secretome, impaired re-epithelialisation and fibroblast persistence [5, 6]. All of which strongly supports a key role for senescence in the pathogenesis of IPF
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