{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T16:45:33Z","timestamp":1793119533594,"version":"4.5.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T00:00:00Z","timestamp":1701820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>The abnormal DNA damage response is associated with upregulation of the type-1 interferon (IFN-I) pathway in certain rheumatic diseases. We investigated whether such aberrant mechanisms operate in psoriatic arthritis (PsA).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>DNA damage levels were measured by alkaline comet assay in peripheral blood mononuclear cells from 52 PsA patients and age-sex-matched healthy individuals. RNA expression of <jats:italic>IFIT1<\/jats:italic>, <jats:italic>MX1<\/jats:italic> and <jats:italic>IFI44<\/jats:italic>, which are selectively induced by IFN-I, was quantitated by real-time polymerase chain reaction and their composite normalized expression resulted in IFN-I score calculation. RNA expression of <jats:italic>IL1\u03b2<\/jats:italic>, <jats:italic>IL6<\/jats:italic>, <jats:italic>TNF<\/jats:italic>, <jats:italic>IL17A<\/jats:italic> and <jats:italic>IL23A<\/jats:italic> was also assessed in PsA and control subgroups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In PsA, DNA damage accumulation was increased by almost two-fold compared to healthy individuals (olive tail moment arbitrary units, mean \u00b1 SD; 9.42 \u00b1 2.71 <jats:italic>vs<\/jats:italic> 4.88 \u00b1 1.98, p&amp;lt;0.0001). DNA damage levels significantly correlated with serum C-Reactive-protein and <jats:italic>IL6<\/jats:italic> RNA expression in PBMCs. Despite increased DNA damage, the IFN-I score was strikingly lower in PsA patients compared to controls (-0.49 \u00b1 6.99 <jats:italic>vs<\/jats:italic> 4.24 \u00b1 4.26; p&amp;lt;0.0001). No correlation was found between IFN-I pathway downregulation and DNA damage. However, the IFN-I score in a PsA subgroup was lower in those patients with higher <jats:italic>IL1\u03b2<\/jats:italic> expression, as well as in those with higher <jats:italic>TNF<\/jats:italic>\/<jats:italic>IL23A<\/jats:italic> PBMCs expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>DNA damage in PsA correlates with measures of inflammation but is not associated with the IFN-I pathway induction. The unexpected IFN-I downregulation, albeit reminiscent to findings in experimental models of spondyloarthritis, may be implicated in PsA pathogenesis and explained by operation of other cytokines.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1274060","type":"journal-article","created":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T08:18:00Z","timestamp":1701850680000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Type-I interferon pathway and DNA damage accumulation in peripheral blood of patients with psoriatic arthritis"],"prefix":"10.3389","volume":"14","author":[{"given":"George E.","family":"Fragoulis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiotis A.","family":"Ntouros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrianos","family":"Nezos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos I.","family":"Vlachogiannis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iain B.","family":"McInnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria G.","family":"Tektonidou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charalampos","family":"Skarlis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vassilis L.","family":"Souliotis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clio P.","family":"Mavragani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petros P.","family":"Sfikakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,12,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1759720X20976975","DOI":"10.1177\/1759720X20976975","article-title":"Higher depression rates and similar cardiovascular comorbidity in psoriatic arthritis compared with rheumatoid arthritis and diabetes mellitus","volume":"12","author":"Fragoulis","year":"2020","journal-title":"Ther Adv Musculoskelet Dis"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-022-00776-6","article-title":"Psoriatic arthritis from a mechanistic perspective","volume":"18","author":"Schett","year":"2022","journal-title":"Nat Rev Rheumatol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.130376","article-title":"Patients with systemic sclerosis present increased DNA damage differentially associated with DNA repair gene polymorphisms","volume":"41","author":"Palomino","year":"2014","journal-title":"J Rheumatol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20082251","article-title":"Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis","volume":"206","author":"Shao","year":"2009","journal-title":"J Exp Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21010055","article-title":"DNA damage response and oxidative stress in systemic autoimmunity","volume":"21","author":"Souliotis","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.582401","article-title":"Association between DNA damage response, fibrosis and type I interferon signature in systemic sclerosis","volume":"11","author":"Vlachogiannis","year":"2020","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.01.012","article-title":"DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity","volume":"42","author":"Hartlova","year":"2015","journal-title":"Immunity."},{"key":"B8","doi-asserted-by":"publisher","first-page":"102949","DOI":"10.1016\/j.autrev.2021.102949","article-title":"Unraveling the complexities of psoriatic arthritis by the use of -Omics and their relevance for clinical care","volume":"20","author":"Grivas","year":"2021","journal-title":"Autoimmun Rev"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2014-207187","article-title":"PTPN22 is associated with susceptibility to psoriatic arthritis but not psoriasis: evidence for a further PsA-specific risk locus","volume":"74","author":"Bowes","year":"2015","journal-title":"Ann Rheum Dis"},{"key":"B10","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.cytogfr.2021.12.002","article-title":"Participation of interferons in psoriatic inflammation","volume":"64","author":"Gu","year":"2022","journal-title":"Cytokine Growth Factor Rev"},{"key":"B11","doi-asserted-by":"publisher","first-page":"154605","DOI":"10.1016\/j.cyto.2018.11.022","article-title":"The influence of interferon on healthy and diseased skin","volume":"132","author":"Hile","year":"2020","journal-title":"Cytokine"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01936","article-title":"Anti-LL37 antibodies are present in psoriatic arthritis (PsA) patients: new biomarkers in psA","volume":"9","author":"Frasca","year":"2018","journal-title":"Front Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0128262","article-title":"Gene expression profiling in peripheral blood cells and synovial membranes of patients with psoriatic arthritis","volume":"10","author":"Dolcino","year":"2015","journal-title":"PloS One"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2022-002687","article-title":"Interferon signature in systemic autoimmune diseases: what does it mean","volume":"8","author":"Nocturne","year":"2022","journal-title":"RMD Open"},{"key":"B15","doi-asserted-by":"publisher","first-page":"108765","DOI":"10.1016\/j.clim.2021.108765","article-title":"Effective DNA damage response after acute but not chronic immune challenge: SARS-CoV-2 vaccine versus Systemic Lupus Erythematosus","volume":"229","author":"Ntouros","year":"2021","journal-title":"Clin Immunol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.jaut.2015.07.002","article-title":"Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis","volume":"63","author":"Nezos","year":"2015","journal-title":"J Autoimmun"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2016.00175","article-title":"DNA repair and cytokines: TGF-beta, IL-6, and thrombopoietin as different biomarkers of radioresistance","volume":"6","author":"Centurione","year":"2016","journal-title":"Front Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-022-01763-8","article-title":"DNA damage induces STING mediated IL-6-STAT3 survival pathway in triple-negative breast cancer cells and decreased survival of breast cancer patients","volume":"27","author":"Vasiyani","year":"2022","journal-title":"Apoptosis"},{"key":"B19","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s13075-020-2111-8","article-title":"A set of serum markers detecting systemic inflammation in psoriatic skin, entheseal, and joint disease in the absence of C-reactive protein and its link to clinical disease manifestations","volume":"22","author":"Sokolova","year":"2020","journal-title":"Arthritis Res Ther"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1759720X221122417","DOI":"10.1177\/1759720X221122417","article-title":"Normal C-reactive protein in active psoriatic arthritis: results from real-world clinical practice","volume":"14","author":"Gialouri","year":"2022","journal-title":"Ther Adv Musculoskelet Dis"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.06.013","article-title":"The autoimmunity-associated gene PTPN22 potentiates toll-like receptor-driven, type 1 interferon-dependent immunity","volume":"39","author":"Wang","year":"2013","journal-title":"Immunity"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/art.38995","article-title":"Comparative genomic profiling of synovium versus skin lesions in psoriatic arthritis","volume":"67","author":"Belasco","year":"2015","journal-title":"Arthritis Rheumatol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/nature06116","article-title":"Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide","volume":"449","author":"Lande","year":"2007","journal-title":"Nature"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1089\/jir.1994.14.229","article-title":"The type I interferon system is locally activated in psoriatic lesions","volume":"14","author":"Schmid","year":"1994","journal-title":"J Interferon Res"},{"key":"B25","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1046\/j.0022-202X.2003.22113.x","article-title":"In psoriasis lesional skin the type I interferon signaling pathway is activated, whereas interferon-alpha sensitivity is unaltered","volume":"122","author":"van der Fits","year":"2004","journal-title":"J Invest Dermatol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20050500","article-title":"Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production","volume":"202","author":"Nestle","year":"2005","journal-title":"J Exp Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/nature23470","article-title":"Mitotic progression following DNA damage enables pattern recognition within micronuclei","volume":"548","author":"Harding","year":"2017","journal-title":"Nature"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/nature23449","article-title":"cGAS surveillance of micronuclei links genome instability to innate immunity","volume":"548","author":"Mackenzie","year":"2017","journal-title":"Nature"},{"key":"B29","doi-asserted-by":"publisher","first-page":"108335","DOI":"10.1016\/j.mrrev.2020.108335","article-title":"Micronuclei, inflammation and auto-immune disease","volume":"786","author":"Kirsch-Volders","year":"2020","journal-title":"Mutat Res Rev Mutat Res"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/art.20798","article-title":"Coordinate overexpression of interferon-alpha-induced genes in systemic lupus erythematosus","volume":"50","author":"Kirou","year":"2004","journal-title":"Arthritis Rheumatol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1209724109","article-title":"Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseases","volume":"109","author":"Hall","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1114981109","article-title":"Systematic identification of type I and type II interferon-induced antiviral factors","volume":"109","author":"Liu","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/art.38628","article-title":"Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type I and type II interferon signatures","volume":"66","author":"Chiche","year":"2014","journal-title":"Arthritis Rheumatol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kex490","article-title":"Systemic interferon type I and type II signatures in primary Sjogren's syndrome reveal differences in biological disease activity","volume":"57","author":"Bodewes","year":"2018","journal-title":"Rheumatol (Oxford)"},{"key":"B35","doi-asserted-by":"publisher","first-page":"374312","DOI":"10.1186\/ar2887","article-title":"Development of potential pharmacodynamic and diagnostic markers for anti-IFN-alpha monoclonal antibody trials in systemic lupus erythematosus","volume":"2009","author":"Yao","year":"2009","journal-title":"Hum Genomics Proteomics"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/art.21890","article-title":"Functional assay of type I interferon in systemic lupus erythematosus plasma and association with anti-RNA binding protein autoantibodies","volume":"54","author":"Hua","year":"2006","journal-title":"Arthritis Rheumatol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20021553","article-title":"Interferon and granulopoiesis signatures in systemic lupus erythematosus blood","volume":"197","author":"Bennett","year":"2003","journal-title":"J Exp Med"},{"key":"B38","doi-asserted-by":"publisher","first-page":"109679","DOI":"10.1016\/j.clim.2023.109679","article-title":"Distinct innate and adaptive immunity phenotypic profile at the circulating single-cell level in Psoriatic Arthritis","volume":"253","author":"Fragoulis","year":"2023","journal-title":"Clin Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.02.006","article-title":"Type I interferon inhibits interleukin-1 production and inflammasome activation","volume":"34","author":"Guarda","year":"2011","journal-title":"Immunity"},{"key":"B40","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/nri3581","article-title":"Regulation of type I interferon responses","volume":"14","author":"Ivashkiv","year":"2014","journal-title":"Nat Rev Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1002\/art.38318","article-title":"Reverse interferon signature is characteristic of antigen-presenting cells in human and rat spondyloarthritis","volume":"66","author":"Fert","year":"2014","journal-title":"Arthritis Rheumatol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.902853","article-title":"Antiviral activities of interleukin-27: A partner for interferons","volume":"13","author":"Amsden","year":"2022","journal-title":"Front Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.093724","article-title":"Exposure to nuclear antigens contributes to the induction of humoral autoimmunity during tumour necrosis factor alpha blockade","volume":"68","author":"Cantaert","year":"2009","journal-title":"Ann Rheum Dis"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1111\/jdv.12240","article-title":"Effects of adalimumab therapy in adult subjects with moderate-to-severe psoriasis on Th17 pathway","volume":"28","author":"Balato","year":"2014","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01440","article-title":"Type1 interferons potential initiating factors linking skin wounds with psoriasis pathogenesis","volume":"10","author":"Zhang","year":"2019","journal-title":"Front Immunol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"196","DOI":"10.3390\/cancers13020196","article-title":"Type I interferons as joint regulators of tumor growth and obesity","volume":"13","author":"Gessani","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.nut.2012.04.019","article-title":"Decreased interferon-alpha and interferon-beta production in obesity and expression of suppressor of cytokine signaling","volume":"29","author":"Teran-Cabanillas","year":"2013","journal-title":"Nutrition"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2022-222370","article-title":"Interferon-alpha-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming","volume":"81","author":"Cooles","year":"2022","journal-title":"Ann Rheum Dis"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.964274","article-title":"Combined - whole blood and skin fibroblasts- transcriptomic analysis in Psoriatic Arthritis reveals molecular signatures of activity, resistance and early response to treatment","volume":"13","author":"Grivas","year":"2022","journal-title":"Front Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1274060\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T08:18:06Z","timestamp":1701850686000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1274060\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,6]]},"references-count":49,"alternative-id":["10.3389\/fimmu.2023.1274060"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1274060","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,6]]},"article-number":"1274060"}}