cGAS: a novel therapeutic target in systemic sclerosis-associated interstitial lung disease

Innate immune aberrations have emerged as key drivers of pulmonary fibrosis in patients with interstitial lung disease (ILD) associated with systemic sclerosis (SSc) [1–3]. The innate immune system is triggered by pattern recognition receptors (PRRs) which recognise epitopes named pathogen-associated molecular patterns (PAMPs) and endogenous ligands named danger-associated molecular patterns (DAMPs). PAMPs are derived from microbes, while DAMPs are released after cellular stress or recurring tissue injury [4]. A previous study has shown that a ligand for intracellular DNA-sensing PRRs modulated fibroblast activation through α-smooth muscle actin expression and the release of their mitochondrial DNA [1]. This observation was more evident in SSc-ILD-derived fibroblasts [1]. Plasma mitochondrial DNA concentrations were increased in two independent cohorts of patients with SSc-ILD and positively associated with both toll-like receptor 9 (TLR9) and cGAS (cytosolic cyclic GMP-AMP synthase)–STING (stimulator of interferon genes) activation [1]. Of note, it has been demonstrated that TLR9 and cGAS–STING signalling pathways lead to an intracellular DNA-driven immune response which is characterised by increased production of type I interferons and interleukin (IL)-6 [5, 6].