Self DNA perpetuates IPF lung fibroblast senescence in a cGAS-dependent manner

Michael Schuliga, Jane Read, Kaj Ec Blokland, David W Waters, Janette Burgess, Cecilia Prele, Steven E Mutsaers, Jade Jaffar, Glen Westall, Andrew Reid, Allen James, Christopher Grainge, Darryl A Knight

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    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. This study examines the contributions of cGAS and self DNA to the senescence of lung fibroblasts from IPF patients (IPF-LFs) and healthy 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 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.

    Original languageEnglish
    JournalClinical Science
    DOIs
    Publication statusE-pub ahead of print - 27 Mar 2020

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