Abstract
Increased endogenous DNA damage and type I interferon pathway activation have been implicated in systemic sclerosis (SSc) pathogenesis. Because experimental evidence suggests an interplay between DNA damage response/repair (DDR/R) and immune response, we hypothesized that deregulated DDR/R is associated with a 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 break 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 score (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.
Highlights
The pathogenesis of systemic sclerosis (SSc) is a complex interplay of immune system activation, tissue fibrosis, and vasculopathy [1,2,3,4]
Endogenous DNA damage was significantly higher in untreated patients with diffuse (Olive tail moment; 14.7 ± 7.0) and limited SSc (9.5 ± 4.1) as well as in SSc patients treated with cytotoxic drugs (15.0 ± 5.4) (P
We found that, compared with normal cells, peripheral blood mononuclear cells (PBMCs) from SSc patients showed significantly higher levels of both oxidative stress and AP sites
Summary
The pathogenesis of systemic sclerosis (SSc) is a complex interplay of immune system activation, tissue fibrosis, and vasculopathy [1,2,3,4]. Major sources of endogenous DNA damage include, among others, oxidative stress mediated mainly by reactive oxygen species (ROS). Oxidative stress can induce single-strand DNA breaks (SSBs) that can be converted to cytotoxic double-strand DNA breaks (DSBs) when replication forks come across SSBs. SSc patients are characterized by increased ROS production in the skin, visceral fibroblasts, and endothelial cells [7, 8]. ROS can activate endothelial cells, leading to vascular hyper-reactivity, endothelial cell apoptosis, and impaired angiogenesis [7]. ROS act on differentiation and proliferation of fibroblasts and promote synthesis of extracellular matrix proteins leading to fibrosis [9]. ROS promote an autoimmune response through the genesis of neoepitopes and the activation of B and T lymphocytes and macrophages [7]
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