Association Between DNA Damage Response, Fibrosis and Type I Interferon Signature in Systemic Sclerosis

Nikolaos I Vlachogiannis; Maria Pappa; Panagiotis A Ntouros; Adrianos Nezos; Clio P Mavragani; Vassilis L Souliotis; Petros P Sfikakis

doi:10.3389/fimmu.2020.582401

Association Between DNA Damage Response, Fibrosis and Type I Interferon Signature in Systemic Sclerosis

Front Immunol. 2020 Oct 2:11:582401. doi: 10.3389/fimmu.2020.582401. eCollection 2020.

Authors

Nikolaos I Vlachogiannis^{1

2}, Maria Pappa^{1

2}, Panagiotis A Ntouros^{1

2}, Adrianos Nezos³, Clio P Mavragani^{2

3}, Vassilis L Souliotis^{1

4}, Petros P Sfikakis^{1

2}

Affiliations

¹ First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece.
² Joint Academic Rheumatology Program, National and Kapodistrian University of Athens Medical School, Athens, Greece.
³ Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
⁴ Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece.

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.

Keywords: DNA damage response and repair network; fibrosis; oxidative stress; systemic sclerosis (scleroderma); type I interferon (IFN).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Apoptosis / genetics
Autoantibodies / metabolism
DNA Damage
DNA Repair / genetics
Female
Fibrosis
Humans
Interferon Type I / genetics*
Interferon Type I / metabolism
Lung / pathology*
Male
Middle Aged
Oxidative Stress / genetics
Scleroderma, Systemic / genetics*
Scleroderma, Systemic / immunology

Substances

Autoantibodies
Interferon Type I