Association Between DNA Damage Response, Fibrosis and Type I Interferon Signature in Systemic Sclerosis
Nikolaos I. Vlachogiannis, Μαρία Παππά, Panagiotis A. Ntouros, Adrianos Nezos, Clio P. Mavragani, Vassilis L. Souliotis, Petros P. Sfikakis
Abstract
Increased endogenous DNA damage and type I interferon pathway activation have been implicated in Systemic Sclerosis (SSc) pathogenesis. Since experimental evidence suggests an interplay between DNA damage response/repair (DDR/R) and immune response, we hypothesized that deregulated DDR/R is associated with type I interferon signature and/or fibrosis extent in SSc. DNA damage levels, oxidative stress, induction of abasic sites and the efficiency of DNA double-strand breaks repair (DSB/R) and nucleotide excision repair (NER) were assessed in peripheral blood mononuclear cells (PBMCs) derived from 37 SSc patients and 55 healthy controls; expression of DDR/R-associated genes and type I interferon-induced genes was also quantified. Endogenous DNA damage was significantly higher in untreated diffuse or limited SSc (Olive Tail Moment; 14.7±7.0 and 9.5±4.1, respectively), as well as in patients under cytotoxic treatment (15.0±5.4), but not in very-early-onset SSc (5.6±1.2) compared with controls (4.9±2.6). Moreover, patients with pulmonary fibrosis had significantly higher DNA damage levels than those without (12.6±5.8 vs 8.8±4.8, respectively). SSc patients displayed increased oxidative stress and abasic sites, defective DSB/R but not NER capacity, downregulation of genes involved in DSB/R (MRE11A, PRKDC) and base excision repair (PARP1, XRCC1), and upregulation of apoptosis-related genes (BAX, BBC3). Individual levels of DNA damage in SSc PBMCs correlated significantly with the corresponding mRNA expression of type I interferon-induced genes (IFIT1, IFI44 and MX1, r=0.419-0.490), as well as with corresponding skin involvement extent, by modified Rodnan skin scores (r=0.481). In conclusion, defective DDR/R may exert a fuel-on-fire effect on type-I interferon pathway activation and contribute to tissue fibrosis in SSc.