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Rheumatology International

Erschienen in:

26.07.2020 | Review

Pulmonary involvement in systemic sclerosis: exploring cellular, genetic and epigenetic mechanisms

verfasst von: Bohdana Doskaliuk, Liubomyr Zaiats, Roman Yatsyshyn, Petro Gerych, Nataliia Cherniuk, Olena Zimba

Erschienen in: Rheumatology International | Ausgabe 10/2020

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Abstract

Systemic sclerosis (SSc) is a chronic progressive autoimmune disease characterized by immune inflammation, vasculopathy, and fibrosis. There are still numerous uncertainties in the understanding of disease initiation and progression. Pulmonary involvement in SSc, and particularly pulmonary fibrosis, is critical for all organ systems affections in this disease. This review is aimed to describe and analyze new findings in the pathophysiology of SSc-associated pulmonary involvement and to explore perspective diagnostic and therapeutic strategies. A myriad of cellular interactions is explored in the dynamics of progressive interstitial lung disease (ILD) and pulmonary hypertension (PH) in SSc. The role of exosomes, microvesicles, and apoptotic bodies is examined and the impact of micro and long non-coding RNAs, DNA methylation, and histone modification in SSc is discussed.

Bergamasco A, Hartmann N, Wallace L, Verpillat P (2019) Epidemiology of systemic sclerosis and systemic sclerosis-associated interstitial lung disease. Clin Epidemiol 11:257–273. https://doi.org/10.2147/CLEP.S191418CrossRefPubMedPubMedCentral

Kang GW, Jung KH, Lee YS, Kim HJ, Yoon DY, Lee SH et al (2018) Incidence, prevalence, mortality and causes of death in systemic sclerosis in Korea: a nationwide population-based study. Br J Dermatol 178(1):e37e9. https://doi.org/10.1111/bjd.15838CrossRef

Ingegnoli F, Ughi N, Mihai C (2018) Update on the epidemiology, risk factors, and disease outcomes of systemic sclerosis. Best Pract Res Clin Rheumatol 32(2):223–240. https://doi.org/10.1016/j.berh.2018.08.005CrossRefPubMed

Denton CP, Wells AU, Coghlan JG (2018) Major lung complications of systemic sclerosis. Nat Rev Rheumatol 14(9):511–527. https://doi.org/10.1038/s41584-018-0062-0CrossRefPubMed

Elhai M, Meune C, Boubaya M, Avouac J, Hachulla E, Balbir-Gurman A, Riemekasten G, Airò P, Joven B, Vettori S, Cozzi F (2017) Mapping and predicting mortality from systemic sclerosis. Ann Rheum Dis 76(11):1897–1905. https://doi.org/10.1136/annrheumdis-2017-211448CrossRefPubMed

Pokeerbux MR, Giovannelli J, Dauchet L, Mouthon L, Agard C, Lega JC, Allanore Y, Jego P, Bienvenu B, Berthier S, Mekinian A (2019) Survival and prognosis factors in systemic sclerosis: data of a French multicenter cohort, systematic review, and meta-analysis of the literature. Arthritis Res Ther 21(1):86. https://doi.org/10.1186/s13075-019-1867-1CrossRefPubMedPubMedCentral

Sierra-Sepúlveda A, Esquinca-González A, Benavides-Suárez SA, Sordo-Lima DE, Caballero-Islas AE, Cabral-Castañeda AR, Rodríguez-Reyna TS (2019) Systemic sclerosis pathogenesis and emerging therapies, beyond the fibroblast. Biomed Res Int. https://doi.org/10.1155/2019/4569826CrossRefPubMedPubMedCentral

Akter T, Silver RM, Bogatkevich GS (2014) Recent advances in understanding the pathogenesis of scleroderma-interstitial lung disease. Curr Rheumatol Rep 16(4):411. https://doi.org/10.1007/s11926-014-0411-1CrossRefPubMed

Homer RJ, Herzog EL (2010) Recent advances in pulmonary fibrosis: implications for scleroderma. Curr Opin Rheumatol 22(6):683–689. https://doi.org/10.1097/BOR.0b013e32833ddcc9CrossRefPubMed

10.

Morales-Cárdenas A, Pérez-Madrid C, Arias L, Ojeda P, Mahecha MP, Rojas-Villarraga A, Carrillo-Bayona JA, Anaya JM (2016) Pulmonary involvement in systemic sclerosis. Autoimmun Rev 15(11):1094–1108. https://doi.org/10.1007/s00296-016-3636-7CrossRefPubMed

11.

Perelas A, Silver RM, Arrossi AV, Highland KB (2020) Systemic sclerosis-associated interstitial lung disease. Lancet Respir Med 8(3):304–320. https://doi.org/10.1016/S2213-2600(19)30480-1CrossRefPubMed

12.

Ahmed S, Pattanaik SS, Rai MK, Nath A, Agarwal V (2018) Interstitial lung disease in systemic sclerosis: insights into pathogenesis and evolving therapies. Mediterr J Rheumatol 29(3):140–147. https://doi.org/10.31138/mjr.29.3.140CrossRefPubMedPubMedCentral

13.

Schoenfeld SR, Castelino FV (2017) Evaluation and management approaches for scleroderma lung disease. Ther Adv Respir Dis 11(8):327–340. https://doi.org/10.1177/1753465817713680CrossRefPubMedPubMedCentral

14.

Gasparyan AY, Ayvazyan L, Blackmore H et al (2011) Writing a narrative biomedical review: considerations for authors, peer reviewers, and editors. Rheumatol Int 31:1409–1417. https://doi.org/10.1007/s00296-011-1999-3CrossRefPubMed

15.

Giacomelli R, Liakouli V, Berardicurti O, Ruscitti P, Di Benedetto P, Carubbi F, Guggino G, Di Bartolomeo S, Ciccia F, Triolo G, Cipriani P (2017) Interstitial lung disease in systemic sclerosis: current and future treatment. Rheumatol Int 37(6):853–863. https://doi.org/10.1007/s00296-016-3636-7CrossRefPubMed

16.

Bhattacharyya S, Wei J, Varga J (2012) Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat Rev Rheumatol 8(1):42. https://doi.org/10.1038/nrrheum.2011.149CrossRef

17.

Servettaz A, Goulvestre C, Kavian N et al (2009) Selective oxidation of DNA topoisomerase 1 induces systemic sclerosis in the mouse. J Immunol 182:5855–5864. https://doi.org/10.4049/jimmunol.0803705CrossRefPubMed

18.

Yamamoto T, Takagawa S, Katayama I et al (1999) Animal model of sclerotic skin. Local injections of bleomycin induce sclerotic skin mimicking scleroderma. J Investig Dermatol 112:456–462. https://doi.org/10.1046/j.1523-1747.1999.00528.xCrossRefPubMed

19.

Spadoni T, Svegliati Baroni S, Amico D, Albani L, Moroncini G, Avvedimento EV, Gabrielli A (2015) A reactive oxygen species–mediated loop maintains increased expression of NADPH oxidases 2 and 4 in skin fibroblasts from patients with systemic sclerosis. Arthritis Rheumatol 67(6):1611–1622. https://doi.org/10.1002/art.39084CrossRefPubMed

20.

Sun Z, Gong X, Zhu H et al (2014) Inhibition of Wnt/β-catenin signaling promotes engraftment of mesenchymal stem cells to repair lung injury. J Cell Physiol 229:213–224. https://doi.org/10.1002/jcp.24436CrossRefPubMed

21.

Ruiz XD, Mlakar LR, Yamaguchi Y et al (2012) Syndecan-2 is a novel target of insulin-like growth factor binding protein-3 and is over-expressed in fibrosis. PLoS ONE 7:e43049. https://doi.org/10.1371/journal.pone.0043049CrossRefPubMedPubMedCentral

22.

Lafyatis R (2014) Transforming growth factor β—at the centre of systemic sclerosis. Nat Rev Rheumatol 10(12):706–719. https://doi.org/10.1038/nrrheum.2014.137CrossRefPubMed

23.

Midgley AC, Rogers M, Hallett MB, Clayton A, Bowen T, Phillips AO, Steadman R (2013) Transforming growth factor-β1 (TGF-β1)-stimulated fibroblast to myofibroblast differentiation is mediated by hyaluronan (HA)-facilitated epidermal growth factor receptor (EGFR) and CD44 co-localization in lipid rafts. J Biol Chem 288(21):14824–14838. https://doi.org/10.1074/jbc.M113.451336CrossRefPubMedPubMedCentral

24.

Baraut J, Farge D, Jean-Louis F, Masse I, Grigore EI, Arruda LC, Lamartine J, Verrecchia F, Michel L (2015) Transforming growth factor-β increases interleukin-13 synthesis via GATA-3 transcription factor in T-lymphocytes from patients with systemic sclerosis. Arthritis Res Ther 17(1):196. https://doi.org/10.1186/s13075-015-0708-0CrossRefPubMedPubMedCentral

25.

Chaudhary NI, Roth GJ, Hilberg F et al (2007) Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis. Eur Respir J 29:976–985. https://doi.org/10.1183/09031936.00152106CrossRefPubMed

26.

Ihn H (2008) Autocrine TGF-β signaling in the pathogenesis of systemic sclerosis. J Dermatol Sci 49:103–113. https://doi.org/10.1016/j.jdermsci.2007.05.014CrossRefPubMed

27.

Phan SH (2002) The myofibroblast in pulmonary fibrosis. Chest 122(6):286S–289S. https://doi.org/10.1378/chest.122.6_suppl.286SCrossRefPubMed

28.

Baroni SS, Santillo M, Bevilacqua F, Luchetti M, Spadoni T, Mancini M, Fraticelli P, Sambo P, Funaro A, Kazlauskas A, Avvedimento EV (2006) Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 354(25):2667–2676. https://doi.org/10.1056/NEJMoa052955CrossRefPubMed

29.

Valenzi E, Bulik M, Tabib T, Morse C, Sembrat J, Bittar HT, Rojas M, Lafyatis R (2019) Single-cell analysis reveals fibroblast heterogeneity and myofibroblasts in systemic sclerosis-associated interstitial lung disease. Ann Rheum Dis 78(10):1379–1387. https://doi.org/10.1136/annrheumdis-2018-214865CrossRefPubMed

30.

Distler O, Highland KB, Gahlemann M et al (2019) Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med 380(26):2518–2528. https://doi.org/10.1056/NEJMoa1903076CrossRefPubMed

31.

Mor A, Salto MS, Katav A, Barashi N, Edelshtein V, Manetti M, Levi Y, George J, Matucci-Cerinic M (2019) Blockade of CCL24 with a monoclonal antibody ameliorates experimental dermal and pulmonary fibrosis. Ann Rheum Dis 78(9):1260–1268. https://doi.org/10.1136/annrheumdis-2019-215119CrossRefPubMed

32.

Kilinc AA, Arslan A, Yildiz M et al (2019) Serum KL-6 level as a biomarker of interstitial lung disease in childhood connective tissue diseases: a pilot study. Rheumatol Int. https://doi.org/10.1007/s00296-019-04485-4CrossRefPubMed

33.

Bonhomme O, André B, Gester F, de Seny D, Moermans C, Struman I, Louis R, Malaise M, Guiot J (2019) Biomarkers in systemic sclerosis-associated interstitial lung disease: review of the literature. Rheumatology 58(9):1534–1546. https://doi.org/10.1093/rheumatology/kez230CrossRefPubMedPubMedCentral

34.

Menon B, Tiwari M, Gopi A, Raj P, Panwar K (2018) Serum Krebs von den Lungen-6 (KL-6): a promising biomarker in sarcoidosis. MOJ Curr Res Rev 1(2):1. https://doi.org/10.15406/mojcrr.2018.01.00009CrossRef

35.

Lanzarone N, Gentili F, Alonzi V, Bergantini L, d’Alessandro M, Rottoli P, Refini RM, Pieroni M, Vietri L, Bianchi F, Mazzei MA (2020) Bronchoalveolar lavage and serum KL-6 concentrations in chronic hypersensitivity pneumonitis: correlations with radiological and immunological features. Intern Emerg Med 20:1–8. https://doi.org/10.1007/s11739-020-02281-8CrossRef

36.

Oguz EO, Kucuksahin O, Turgay M et al (2016) Association of serum KL-6 levels with interstitial lung disease in patients with connective tissue disease: a cross-sectional study. Clin Rheumatol 35:6636. https://doi.org/10.1007/s10067-015-3167-8CrossRef

37.

Kuwana M, Shirai Y, Takeuchi T (2016) Elevated serum Krebs von den Lungen-6 in early disease predicts subsequent deterioration of pulmonary function in patients with systemic sclerosis and interstitial lung disease. J Rheumatol 43:1825–1831. https://doi.org/10.3899/jrheum.160339CrossRefPubMed

38.

Benyamine A, Heim X, Resseguier N, Bertin D, Gomez C, Ebbo M, Harlé JR, Kaplanski G, Rossi P, Bardin N, Granel B (2018) Elevated serum Krebs von den Lungen-6 in systemic sclerosis: a marker of lung fibrosis and severity of the disease. Rheumatol Int 38(5):813–819. https://doi.org/10.1007/s00296-018-3987-3CrossRefPubMed

39.

Elhai M, Hoffmann-Vold AM, Avouac J et al (2019) Performance of candidate serum biomarkers for systemic sclerosis associated-interstitial lung disease. Arthritis Rheumatol 71:972–982. https://doi.org/10.1002/art.40815CrossRefPubMed

40.

Doishita S, Inokuma S, Asashima H et al (2011) Serum KL-6 level as an indicator of active or inactive interstitial pneumonitis associated with connective tissue diseases. Intern Med 50:2889–2892. https://doi.org/10.2169/internalmedicine.50.5866CrossRefPubMed

41.

Salazar GA, Kuwana M, Wu M, Estrada-Y-Martin RM, Ying J, Charles J, Mayes MD, Assassi S (2018) KL-6 but not CCL-18 is a predictor of early progression in systemic sclerosis-related interstitial lung disease. J Rheumatol 45(8):1153–1158. https://doi.org/10.3899/jrheum.170518CrossRefPubMedPubMedCentral

42.

Asano Y, Ihn H, Yamane K, Yazawa N, Kubo M, Fujimoto M, Tamaki K (2001) Clinical significance of surfactant protein D as a serum marker for evaluating pulmonary fibrosis in patients with systemic sclerosis. Arthritis Rheumatol 44(6):1363–1369. https://doi.org/10.1002/1529-0131(200106)44:6%3c1363:AID-ART229%3e3.0.CO;2-5CrossRef

43.

Hant FN, Ludwicka-Bradley A, Wang H-J et al (2009) Surfactant protein D and KL-6 as serum biomarkers of interstitial lung disease in patients with scleroderma. J Rheumatol 3636:773–780. https://doi.org/10.3899/jrheum.080633CrossRef

44.

Koichi Y, Minoru H, Kazuhiko T, Shinichi S (2004) Comparative study of serum surfactant protein-D and KL-6 concentrations in patients with systemic sclerosis as markers of monitoring activity of pulmonary fibrosis. J Rheumatol 31:1112–1120

45.

Yamakawa H, Hagiwara E, Kitamura H, Yamanaka Y, Ikeda S, Sekine A, Baba T, Okudela K, Iwasawa T, Takemura T, Kuwano K (2017) Serum KL-6 and surfactant protein-D as monitoring and predictive markers of interstitial lung disease in patients with systemic sclerosis and mixed connective tissue disease. J Thorac Dis 9(2):362–371. https://doi.org/10.21037/jtd.2017.02.48CrossRefPubMedPubMedCentral

46.

Takahashi H, Kuroki Y, Tanaka H, Saito T, Kurokawa K, Chiba H, Sagawa A, Nagae H, Abe S (2000) Serum levels of surfactant proteins A and D are useful biomarkers for interstitial lung disease in patients with progressive systemic sclerosis. Am J Respir Crit Care Med 162(1):258–263. https://doi.org/10.1164/ajrccm.162.1.9903014CrossRefPubMed

47.

Yan C, Deng C, Liu X, Chen Y, Ye J, Cai R, Shen Y, Tang H (2018) TNF-α induction of IL-6 in alveolar type II epithelial cells: contributions of JNK/c-Jun/AP-1 element, C/EBPδ/C/EBP binding site and IKK/NF-κB p65/κB site. Mol Immunol 101:585–596. https://doi.org/10.1016/j.molimm.2018.05.004CrossRefPubMed

48.

Shastri MD, Stewart N, Horne J, Peterson GM, Gueven N, Sohal SS, Patel RP (2015) In-vitro suppression of IL-6 and IL-8 release from human pulmonary epithelial cells by non-anticoagulant fraction of enoxaparin. PLoS One 10(5):e0126763. https://doi.org/10.1371/journal.pone.0126763CrossRefPubMedPubMedCentral

49.

Shukla SD, Mahmood MQ, Weston S, Latham R, Muller HK, Sohal SS, Walters EH (2017) The main rhinovirus respiratory tract adhesion site (ICAM-1) is upregulated in smokers and patients with chronic airflow limitation (CAL). Respir Res 18(1):6. https://doi.org/10.1186/s12931-016-0483-8CrossRefPubMedPubMedCentral

50.

Kuhn H, Petzold K, Hammerschmidt S, Wirtz H (2014) Interaction of cyclic mechanical stretch and toll-like receptor 4-mediated innate immunity in rat alveolar type II cells. Respirology 19(1):67–73. https://doi.org/10.1111/resp.12149CrossRefPubMed

51.

Wong MH, Johnson MD (2013) Differential response of primary alveolar type I and type II cells to LPS stimulation. PLoS ONE 8(1):e55545. https://doi.org/10.1371/journal.pone.0055545CrossRefPubMedPubMedCentral

52.

Shen YC, Chiu CF, Chow KC, Chen CL, Liaw YC, Yeh SP (2004) Fatal pulmonary fibrosis associated with BCNU: the relative role of platelet-derived growth factor-B, insulin-like growth factor I, transforming growth factor-β 1 and cyclooxygenase-2. Bone Marrow Transpl 34(7):609–614. https://doi.org/10.1038/sj.bmt.1704616CrossRef

53.

Corrin B, Butcher D, McAnulty BJ, Du Bois RM, Black CM, Laurent GJ, Harrison NK (1994) Immunohistochemical localization of transforming growth factor-b1 in the lungs of patients with systemic sclerosis, cryptogenic fibrosing alveolitis and other lung disorders. Histopathology 24:145–150. https://doi.org/10.1111/j.1365-2559.1994.tb01293.xCrossRefPubMed

54.

Makino K, Makino T, Stawski L, Mantero JC, Lafyatis R, Simms R, Trojanowska M (2017) Blockade of PDGF receptors by crenolanib has therapeutic effect in patient fibroblasts and in preclinical models of systemic sclerosis. J Investig Dermatol 137(8):1671–1681. https://doi.org/10.1016/j.jid.2017.03.032CrossRefPubMed

55.

Fang F, Ooka K, Bhattachyya S, Wei J, Wu M, Du P, Lin S, Del Galdo F, Feghali-Bostwick CA, Varga J (2011) The early growth response gene Egr2 (alias Krox20) is a novel transcriptional target of transforming growth factor-β that is up-regulated in systemic sclerosis and mediates profibrotic responses. Am J Pathol 178(5):2077–2090. https://doi.org/10.1016/j.ajpath.2011.01.035CrossRefPubMedPubMedCentral

56.

Novelli F, Neri T, Tavanti L, Armani C, Noce C, Falaschi F, Bartoli ML, Martino F, Palla A, Celi A, Paggiaro P (2014) Procoagulant, tissue factor-bearing microparticles in bronchoalveolar lavage of interstitial lung disease patients: an observational study. PloS One 9(4):e95013. https://doi.org/10.1371/journal.pone.0095013CrossRefPubMedPubMedCentral

57.

Goldmann T, Zissel G, Watz H et al (2018) Human alveolar epithelial cells type II are capable of TGFβ-dependent epithelial-mesenchymal-transition and collagen-synthesis. Respir Res 19(1):138. https://doi.org/10.1186/s12931-018-0841-9CrossRefPubMedPubMedCentral

58.

Bagnato G, Harari S (2015) Cellular interactions in the pathogenesis of interstitial lung diseases. Eur Respir Rev 24(135):102–114. https://doi.org/10.1183/09059180.00003214CrossRefPubMed

59.

Lam AP, Flozak AS, Russell S et al (2011) Nuclear β-catenin is increased in systemic sclerosis pulmonary fibrosis and promotes lung fibroblast migration and proliferation. Am J Respir Cell Mol Biol 45:915–922CrossRefPubMedPubMedCentral

60.

Tan SY, Krasnow MA (2016) Developmental origin of lung macrophage diversity. Development 143(8):1318–1327. https://doi.org/10.1242/dev.129122CrossRefPubMedPubMedCentral

61.

To S, Agarwal SK (2019) Macrophages and cadherins in fibrosis and systemic sclerosis. Curr Opin Rheumatol 31(6):582–588. https://doi.org/10.1097/BOR.0000000000000657CrossRefPubMed

62.

Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8(12):958–969. https://doi.org/10.1038/nri2448CrossRefPubMedPubMedCentral

63.

Bhattacharya S, Aggarwal A (2019) M2 macrophages and their role in rheumatic diseases. Rheumatol Int 39(5):769–780. https://doi.org/10.1007/s00296-018-4120-3CrossRefPubMed

64.

Higashi-Kuwata N, Jinnin M, Makino T et al (2010) Characterization of monocyte/macrophage subsets in the skin and peripheral blood derived from patients with systemic sclerosis. Arthritis Res Ther 12:R128. https://doi.org/10.1186/ar3066CrossRefPubMedPubMedCentral

65.

Mantovani A, Biswas SK, Galdiero MR et al (2013) Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 229:176–185. https://doi.org/10.1002/path.4133CrossRefPubMed

66.

Zhu X, Fang X, Chen W, Han F, Huang Z, Luo B, Gu P, Zhang L, Qiu W, Zeng Y, Rui W (2017) Lower expression of platelet derived growth factor is associated with better overall survival rate of patients with idiopathic nonspecific interstitial pneumonia. J Thorac Dis 9(3):519–528. https://doi.org/10.21037/jtd.2017.02.50CrossRefPubMedPubMedCentral

67.

He J, Mu M, Wang H, Ma H, Tang X, Fang Q, Guo S, Song C (2019) Upregulated IGF-1 in the lungs of asthmatic mice originates from alveolar macrophages. Mol Med Rep 19(2):1266–1271. https://doi.org/10.3892/mmr.2018.9726CrossRefPubMed

68.

Stifano G, Christmann RB (2016) Macrophage involvement in systemic sclerosis: do we need more evidence? Curr Rheumatol Rep 18(1):2. https://doi.org/10.1007/s11926-015-0554-8CrossRefPubMed

69.

Moreno-Moral A, Bagnati M, Koturan S, Ko JH, Fonseca C, Harmston N et al (2018) Changes in macrophage transcriptome associate with systemic sclerosis and mediate GSDMA contribution to disease risk. Ann Rheum Dis 77:596–601. https://doi.org/10.1136/annrheumdis-2017-212454CrossRefPubMed

70.

Lescoat A, Jégo P, Lecureur V (2018) M-CSF and GM-CSF monocyte-derived macrophages in systemic sclerosis: the two sides of the same coin? Ann Rheum Dis 78:e19. https://doi.org/10.1136/annrheumdis-2018-213112CrossRefPubMed

71.

Higashi-Kuwata N, Jinnin M, Makino T, Fukushima S, Inoue Y, Muchemwa FC, Yonemura Y, Komohara Y, Takeya M, Mitsuya H, Ihn H (2010) Characterization of monocyte/macrophage subsets in the skin and peripheral blood derived from patients with systemic sclerosis. Arthritis Res Ther 12(4):R128. https://doi.org/10.1186/ar3066CrossRefPubMedPubMedCentral

72.

Prasse A, Pechkovsky DV, Toews GB, Schafer M, Eggeling S, Ludwig C et al (2007) CCL18 as an indicator of pulmonary fibrotic activity in idiopathic interstitial pneumonias and systemic sclerosis. Arthritis Rheumatol 56(5):1685–1693. https://doi.org/10.1002/art.22559CrossRef

73.

Schupp J, Becker M, Gunther J, Muller-Quernheim J, Riemekasten G, Prasse A (2014) Serum CCL18 is predictive for lung disease progression and mortality in systemic sclerosis. Eur Respir J 43(5):1530–1532. https://doi.org/10.1183/09031936.00131713CrossRefPubMed

74.

Tiev KP, Hua-Huy T, Kettaneh A, GainM Duong-Quy S, Toledano C et al (2011) Serum CC chemokine ligand-18 predicts lung disease worsening in systemic sclerosis. Eur Respir J 38(6):1355–1360. https://doi.org/10.1183/09031936.00004711CrossRefPubMed

75.

Trombetta AC, Soldano S, Contini P et al (2018) A circulating cell population showing both M1 and M2 monocyte/macrophage surface markers characterizes systemic sclerosis patients with lung involvement. Respir Res 19:186. https://doi.org/10.1186/s12931-018-0891-zCrossRefPubMedPubMedCentral

76.

Otsuka K, Yamada K, Taquahashi Y et al (2018) Long-term polarization of alveolar macrophages to a profibrotic phenotype after inhalation exposure to multiwall carbon nanotubes. PLoS ONE 13:e0205702. https://doi.org/10.1371/journal.pone.0205702CrossRefPubMedPubMedCentral

77.

McCubbrey AL, Barthel L, Mohning MP et al (2018) Deletion of c-FLIP from CD11b hi macrophages prevents development of bleomycin-induced lung fibrosis. Am J Respir Cell Mol Biol 58:66–78. https://doi.org/10.1165/rcmb.2017-0154OCCrossRefPubMedPubMedCentral

78.

Nicolosi PA, Tombetti E, Giovenzana A, Donè E, Pulcinelli E, Meneveri R, Tirone M, Maugeri N, Rovere-Querini P, Manfredi AA, Brunelli S (2019) Macrophages guard endothelial lineage by hindering endothelial-to-mesenchymal transition: implications for the pathogenesis of Systemic Sclerosis. J Immunol 203(1):247–258. https://doi.org/10.4049/jimmunol.1800883CrossRefPubMed

79.

Sun C, Chen SY (2018) RGC32 promotes bleomycin-induced systemic sclerosis in a murine disease model by modulating classically activated macrophage function. J Immunol 200(8):2777–2785. https://doi.org/10.4049/jimmunol.1701542CrossRefPubMed

80.

Khanna D, Denton CP, Jahreis A et al (2016) Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet 387:2630–2640. https://doi.org/10.1016/S0140-6736(16)00232-4CrossRefPubMed

81.

Shen P, Fillatreau S (2015) Antibody-independent functions of B cells: a focus on cytokines. Nat Rev Immunol 15(7):441–451. https://doi.org/10.1038/nri3857CrossRefPubMed

82.

Matsushita T, Hamaguchi Y, Hasegawa M, Takehara K, Fujimoto M (2016) Decreased levels of regulatory B cells in patients with systemic sclerosis: association with autoantibody production and disease activity. Rheumatology 55(2):263–267. https://doi.org/10.1093/rheumatology/kev331CrossRefPubMed

83.

Matsushita T, Kobayashi T, Mizumaki K, Kano M, Sawada T, Tennichi M, Okamura A, Hamaguchi Y, Iwakura Y, Hasegawa M, Fujimoto M (2018) BAFF inhibition attenuates fibrosis in scleroderma by modulating the regulatory and effector B cell balance. Sci Adv 4(7):eaas9944. https://doi.org/10.1126/sciadv.aas9944CrossRefPubMedPubMedCentral

84.

Wynn TA (2004) Fibrotic disease and the TH 1/TH 2 paradigm. Nat Rev Immunol 4(8):583–594. https://doi.org/10.1038/nri1412CrossRefPubMedPubMedCentral

85.

Boin F, De Fanis U, Bartlett SJ, Wigley FM, Rosen A, Casolaro V (2008) T cell polarization identifies distinct clinical phenotypes in scleroderma lung disease. Arthritis Rheumatol 58(4):1165–1174. https://doi.org/10.1002/art.23406CrossRef

86.

Ugor E, Simon D, Almanzar G, Pap R, Najbauer J, Németh P, Balogh P, Prelog M, Czirják L, Berki T (2017) Increased proportions of functionally impaired regulatory T cell subsets in systemic sclerosis. J Clin Immunol 184:54–62. https://doi.org/10.1016/j.clim.2017.05.013CrossRef

87.

Fava A, Cimbro R, Wigley FM, Liu QR, Rosen A, Boin F (2016) Frequency of circulating topoisomerase-I-specific CD4 T cells predicts presence and progression of interstitial lung disease in scleroderma. Arthritis Res Ther 18(1):99. https://doi.org/10.1186/s13075-016-0993-2CrossRefPubMedPubMedCentral

88.

Ahmed S, Misra DP, Agarwal V (2019) Interleukin-17 pathways in systemic sclerosis-associated fibrosis. Rheumatol Int 39(7):1135–1143. https://doi.org/10.1007/s00296-019-04317-5CrossRefPubMed

89.

Truchetet ME, Brembilla NC, Montanari E, Allanore Y, Chizzolini C (2011) Increased frequency of circulating Th22 in addition to Th17 and Th2 lymphocytes in systemic sclerosis: association with interstitial lung disease. Arthritis Res Ther 13(5):R166. https://doi.org/10.1186/ar3486CrossRefPubMedPubMedCentral

90.

Hur J, Yang HM, Yoon CH, Lee CS, Park KW, Kim JH, Kim TY, Kim JY, Kang HJ, Chae IH, Oh BH, Park YB, Kim HS (2007) Identification of a novel role of T cells in postnatal vasculogenesis: characterization of endothelial progenitor cell colonies. Circulation 116:1671–1682. https://doi.org/10.1161/CIRCULATIONAHA.107.694778CrossRefPubMed

91.

Kushner EJ, MacEneaney OJ, Morgan RG, Van Engelenburg AM, Van Guilder GP, DeSouza CA (2010) CD31+ T cells represent a functionally distinct vascular T cell phenotype. Blood Cells Mol Dis 44:74–78. https://doi.org/10.1016/j.bcmd.2009.10.009CrossRefPubMed

92.

Lv T, Yang F, Zhang K, Lv M, Zhang Y, Zhu P (2020) The risk of circulating angiogenic T cells and subsets in patients with systemic sclerosis. Int Immunopharmacol 81:1062–1082. https://doi.org/10.1016/j.intimp.2020.106282CrossRef

93.

Łukasik ZM, Makowski M, Makowska JS (2018) From blood coagulation to innate and adaptive immunity: the role of platelets in the physiology and pathology of autoimmune disorders. Rheumatol Int 38(6):959–974. https://doi.org/10.1007/s00296-018-4001-9CrossRefPubMedPubMedCentral

94.

Soydinc S, Turkbeyler IH, Pehlivan Y, Soylu G, Goktepe MF, Bilici M, Zengin O, Kisacik B, Onat AM (2014) Mean platelet volume seems to be a valuable marker in patients with systemic sclerosis. Inflammation 37(1):100–106. https://doi.org/10.1007/s10753-013-9716-xCrossRefPubMed

95.

Kowal-Bielecka O, Kowal K, Lewszuk A, Bodzenta-Lukaszyk A, Walecki J, Sierakowski S (2005) β Thromboglobulin and platelet factor 4 in bronchoalveolar lavage fluid of patients with systemic sclerosis. Ann Rheum Dis 64(3):484–486. https://doi.org/10.1136/ard.2004.022970CrossRefPubMedPubMedCentral

96.

Kim A, Kim Y, Kim GT, Ahn E, So MW, Sohn DH, Lee SG (2020) Platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio as potential makers for digital ulcers and interstitial lung disease in patients with systemic sclerosis: cross-sectional analysis of data from a prospective cohort study. Rheumatol Int 40:1071–1079. https://doi.org/10.1007/s00296-020-04604-6CrossRefPubMed

97.

Nadaud S, Poirier O, Girerd B, Blanc C, Montani D, Eyries M, Imbert-Bismut F, Pacheco A, Vigne J, Tregouet DA, Humbert M (2013) Small platelet microparticle levels are increased in pulmonary arterial hypertension. Eur J Clin Investig 43(1):64–71. https://doi.org/10.1111/eci.12018CrossRef

98.

van Bon L, Affandi AJ, Broen J, Christmann RB, Marijnissen RJ, Stawski L et al (2014) Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N Engl J Med 370:433–443. https://doi.org/10.1056/NEJMoa1114576CrossRefPubMed

99.

Ntelis K, Solomou EE, Sakkas L, Liossis SN, Daoussis D (2017) The role of platelets in autoimmunity, vasculopathy, and fibrosis: implications for systemic sclerosis. Semin Arthritis Rheumatol 47(3):409–417. https://doi.org/10.1016/j.semarthrit.2017.05.004CrossRef

100.

Ciuclan L, Bonneau O, Hussey M, Duggan N, Holmes AM, Good R, Stringer R, Jones P, Morrell NW, Jarai G, Walker C (2011) A novel murine model of severe pulmonary arterial hypertension. Am J Respir Crit Care Med 184(10):1171–1182. https://doi.org/10.1164/rccm.201103-0412OCCrossRefPubMed

101.

Long L, MacLean MR, Jeffery TK, Morecroft I, Yang X, Rudarakanchana N, Southwood M, James V, Trembath RC, Morrell NW (2006) Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice. Circ Res 98(6):818–827. https://doi.org/10.1161/01.RES.0000215809.47923.fdCrossRefPubMed

102.

Ntelis K, Gkizas V, Filippopoulou A, Davlouros P, Alexopoulos D, Andonopoulos AP, Daoussis D (2016) Clopidogrel treatment may associate with worsening of endothelial function and development of new digital ulcers in patients with systemic sclerosis: results from an open label, proof of concept study. BMC Musculoskelet Disord 17:213. https://doi.org/10.1186/s12891-016-1072-1CrossRefPubMedPubMedCentral

103.

Arciniegas E, Frid MG, Douglas IS, Stenmark KR (2007) Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 293(1):L1–L8. https://doi.org/10.1152/ajplung.00378.2006CrossRefPubMed

104.

Wermuth PJ, Carney KR, Mendoza FA, Piera-Velazquez S, Jimenez SA (2017) Endothelial cell-specific activation of transforming growth factor-β signaling in mice induces cutaneous, visceral, and microvascular fibrosis. Lab Investig 97(7):806–818. https://doi.org/10.1038/labinvest.2017.23CrossRefPubMed

105.

Mendoza FA, Piera-Velazquez S, Farber JL, Feghali-Bostwick C, Jimenez SA (2016) Endothelial cells expressing endothelial and mesenchymal cell gene products in lung tissue from patients with systemic sclerosis-associated interstitial lung disease. Arthritis Rheumatol 68(1):210–217. https://doi.org/10.1002/art.39421CrossRefPubMedPubMedCentral

106.

Good RB, Gilbane AJ, Trinder SL, Denton CP, Coghlan G, Abraham DJ, Holmes AM (2015) Endothelial to mesenchymal transition contributes to endothelial dysfunction in pulmonary arterial hypertension. Am J Pathol 185(7):1850–1858. https://doi.org/10.1016/j.ajpath.2015.03.019CrossRefPubMed

107.

Derrett-Smith EC, Dooley A, Gilbane A, Trinder S, Khan K, Baliga R, Holmes A, Hobbs A, Abraham D, Denton CP (2013) Endothelial injury in a transforming growth factor b-dependent mouse model of scleroderma induces pulmonary arterial hypertension. Arthritis Rheumatol 65:2928–2939. https://doi.org/10.1002/art.38078CrossRef

108.

Kuo CF, Luo SF, Yu KH, See LC, Zhang W, Doherty M (2016) Familial risk of systemic sclerosis and co-aggregation of autoimmune diseases in affected families. Arthritis Res Ther 18(1):231. https://doi.org/10.1186/s13075-016-1127-6CrossRefPubMedPubMedCentral

109.

Feghali-Bostwick C, Medsger TA Jr, Wright TM (2003) Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheumatol 48:1956–1963. https://doi.org/10.1002/art.11173CrossRef

110.

Wermuth PJ, Piera-Velazquez S, Rosenbloom J, Jimenez SA (2018) Existing and novel biomarkers for precision medicine in systemic sclerosis. Nat Rev Rheumatol 14(7):421–432. https://doi.org/10.1038/s41584-018-0021-9CrossRefPubMed

111.

Milano A et al (2008) Molecular subsets in the gene expression signatures of scleroderma skin. PLoS ONE 3:e2696. https://doi.org/10.1371/journal.pone.0002696CrossRefPubMedPubMedCentral

112.

Angiolilli C, Marut W, van der Kroef M, Chouri E, Reedquist KA, Radstake TR (2018) New insights into the genetics and epigenetics of systemic sclerosis. Nat Rev Rheumatol 14(11):657–673. https://doi.org/10.1038/s41584-018-0099-0CrossRefPubMed

113.

Lopez-Isac E et al (2016) Brief report: IRF4 newly identified as a common susceptibility locus for systemic sclerosis and rheumatoid arthritis in a cross-disease meta-analysis of genome-wide association studies. Arthritis Rheumatol 68:2338–2344. https://doi.org/10.1002/art.39730CrossRefPubMedPubMedCentral

114.

Mahoney JM et al (2015) Systems level analysis of systemic sclerosis shows a network of immune and profibrotic pathways connected with genetic polymorphisms. PLoS Comput Biol 11:e1004005. https://doi.org/10.1371/journal.pcbi.1004133CrossRefPubMedPubMedCentral

115.

Farina G, Lafyatis D, Lemaire R, Lafyatis R (2010) A four- gene biomarker predicts skin disease in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheumatol 62:580–588. https://doi.org/10.1002/art.27220CrossRef

116.

Christmann RB, Sampaio-Barros P, Stifano G, Borges CL, De Carvalho CR, Kairalla R, Parra ER, Spira A, Simms R, Capellozzi VL, Lafyatis R (2014) Association of interferon-and transforming growth factor β–regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis. Arthritis Rheumatol 66(3):714–725. https://doi.org/10.1002/art.38288CrossRefPubMedPubMedCentral

117.

Tiev KP, Hua-Huy T, Kettaneh A, Gain M, Duong-Quy S, Toledano C et al (2011) Serum CC chemokine ligand-18 predicts lung disease worsening in systemic sclerosis. Eur Respir J 38:1355–1360. https://doi.org/10.1183/09031936.00004711CrossRefPubMed

118.

Hsu E, Shi H, Jordan RM, Lyons-Weiler J, Pilewski JM, Feghali-Bostwick CA (2011) Lung tissues in patients with systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension. Arthritis Rheumatol 63(3):783–794CrossRef

119.

Bernal PJ, Leelavanichkul K, Bauer E, Cao R, Wilson A, Wasserloos KJ et al (2008) Nitric oxide-mediated zinc release contributes to hypoxic regulation of pulmonary vascular tone. Circ Res 102:1575–1583. https://doi.org/10.1161/CIRCRESAHA.108.171264CrossRefPubMedPubMedCentral

120.

Xu Y, Wang W, Tian Y, Liu J, Yang R (2016) Polymorphisms in STAT4 and IRF5 increase the risk of systemic sclerosis: a meta-analysis. Int J Dermatol 55:408–416. https://doi.org/10.1111/ijd.12839CrossRefPubMed

121.

Mak AC et al (2016) Brief report: whole-exome sequencing for identification of potential causal variants for diffuse cutaneous systemic sclerosis. Arthritis Rheumatol 68:2257–2262. https://doi.org/10.1002/art.39721CrossRefPubMedPubMedCentral

122.

Tang L, Chen B, Ma B, Nie S (2014) Association between IRF5 polymorphisms and autoimmune diseases: a meta-analysis. Genet Mol Res 13:4473–4485. https://doi.org/10.4238/2014.june.16.6CrossRefPubMed

123.

Wang J et al (2014) Association of the IRF5 SNP rs2004640 with systemic sclerosis in Han Chinese. Int J Immunopathol Pharmacol 27:635–638. https://doi.org/10.1177/039463201402700420CrossRefPubMed

124.

Zhao W et al (2017) The status of pulmonary fibrosis in systemic sclerosis is associated with IRF5, STAT4, IRAK1, and CTGF polymorphisms. Rheumatol Int 37:1303–1310. https://doi.org/10.1007/s00296-017-3722-5CrossRefPubMed

125.

Ha M, Kim VN (2014) Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol 15(8):509–524. https://doi.org/10.1038/nrm3838CrossRefPubMed

126.

Kim VN, Nam JW (2006) Genomics of microRNA. Trends Genet 22(3):165–173. https://doi.org/10.1016/j.tig.2006.01.003CrossRefPubMed

127.

Brennecke J, Stark A, Russell RB, Cohen SM (2005) Principles of microRNA–target recognition. PLoS Biol 3(3):e85. https://doi.org/10.1371/journal.pbio.0030085CrossRefPubMedPubMedCentral

128.

Chouri E, Servaas NH, Bekker CP, Affandi AJ, Cossu M, Hillen MR, Angiolilli C, Mertens JS, van den Hoogen LL, Silva-Cardoso S, van der Kroef M (2018) Serum microRNA screening and functional studies reveal miR-483-5p as a potential driver of fibrosis in systemic sclerosis. J Autoimmun 89:162–170. https://doi.org/10.1016/j.jaut.2017.12.015CrossRefPubMed

129.

Hsu E, Feghali-Bostwick CA (2008) Insulin-like growth factor-II is increased in systemic sclerosis-associated pulmonary fibrosis and contributes to the fibrotic process via Jun N-terminal kinase- and phosphatidylinositol-3 kinase dependent pathways. Am J Pathol 172(6):1580–1590. https://doi.org/10.2353/ajpath.2008.071021CrossRefPubMedPubMedCentral

130.

Christmann RB, Wooten A, Sampaio-Barros P, Borges CL, Carvalho CR, Kairalla RA, Feghali-Bostwick C, Ziemek J, Mei Y, Goummih S, Tan J (2016) miR-155 in the progression of lung fibrosis in systemic sclerosis. Arthritis Res Ther 18(1):155. https://doi.org/10.1186/s13075-016-1054-6CrossRefPubMedPubMedCentral

131.

Jiang Z, Tao JH, Zuo T, Li XM, Wang GS, Fang X, Xu XL, Li XP (2017) The correlation between miR-200c and the severity of interstitial lung disease associated with different connective tissue diseases. Scand J Rheumatol 46(2):122–129. https://doi.org/10.3109/03009742.2016.1167950CrossRefPubMed

132.

Vreca M, Andjelkovic M, Tosic N, Zekovic A, Damjanov N, Pavlovic S, Spasovski V (2018) Impact of alterations in X-linked IRAK1gene and miR-146a on susceptibility and clinical manifestations in patients with systemic sclerosis. Immunol Lett 204:1–8. https://doi.org/10.1016/j.imlet.2018.10.002CrossRefPubMed

133.

Liu G, Friggeri A, Yang Y, Milosevic J, Ding Q, Thannickal VJ et al (2010) miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J Exp Med 207:1589–1597. https://doi.org/10.1084/jem.20100035CrossRefPubMedPubMedCentral

134.

Izumiya Y, Jinnn M, Kimura Y, Wang Z, Onoue Y, Hanatani S, Araki S, Ihn H, Ogawa H (2015) Expression of Let-7 family microRNAs in skin correlates negatively with severity of pulmonary hypertension in patients with systemic scleroderma. IJC Heart Vasc 8:98–102. https://doi.org/10.1016/j.ijcha.2015.06.006CrossRef

135.

Kawashita Y, Jinnin M, Makino T, Kajihara I, Makino K, Honda N, Masuguchi S, Fukushima S, Inoue Y, Ihn H (2011) Circulating miR-29a levels in patients with scleroderma spectrum disorder. J Dermatol Sci 61(1):67–69. https://doi.org/10.1016/j.jdermsci.2010.11.007CrossRefPubMed

136.

Iwamoto N, Vettori S, Maurer B, BrockM Pachera E, Jüngel A et al (2016) Downregulation of miR-193b in systemic sclerosis regulates the proliferative vasculopathy by urokinase-type plasminogen activator expression. Ann Rheum Dis 75:303–310. https://doi.org/10.1136/annrheumdis-2014-205326CrossRefPubMed

137.

Yao RW, Wang Y, Chen LL (2019) Cellular functions of long noncoding RNAs. Nat Cell Biol 21(5):542–551. https://doi.org/10.1038/s41556-019-0311-8CrossRefPubMed

138.

Takata M, Pachera E, Frank-Bertoncelj M, Kozlova A, Jüngel A, Whitfield ML, Assassi S, Calcagni M, de Vries-Bouwstra J, Huizinga TW, Kurreeman F (2019) OTUD6B-AS1 might be a novel regulator of apoptosis in systemic sclerosis. Front Immunol 10:1100. https://doi.org/10.3389/fimmu.2019.01100CrossRefPubMedPubMedCentral

139.

Wasson CW, Abignano G, Hermes H, Malaab M, Ross RL, Jimenez SA, Chang HY, Feghali-Bostwick CA, del Galdo F (2020) Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH. Ann Rheum Dis 79(4):507–517. https://doi.org/10.1136/annrheumdis-2019-216542CrossRefPubMed

140.

Tsou PS (2019) Epigenetic control of scleroderma: current knowledge and future perspectives. Curr Rheumatol Rep 21(12):69. https://doi.org/10.1007/s11926-019-0877-yCrossRefPubMed

141.

Cedar H, Bergman Y (2009) Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet 10(5):295–304. https://doi.org/10.1038/nrg2540CrossRefPubMed

142.

Ramos PS, Zimmerman KD, Haddad S, Langefeld CD, Medsger TA, Feghali-Bostwick CA (2019) Integrative analysis of DNA methylation in discordant twins unveils distinct architectures of systemic sclerosis subsets. Clin Epigenet 11(1):58. https://doi.org/10.1186/s13148-019-0652-yCrossRef

143.

Altorok N, Tsou PS, Coit P, Khanna D, Sawalha AH (2015) Genome-wide DNA methylation analysis in dermal fibroblasts from patients with diffuse and limited systemic sclerosis reveals common and subset-specific DNA methylation aberrancies. Ann Rheum Dis 74:1612–1620. https://doi.org/10.1136/annrheumdis-2014-205303CrossRefPubMed

144.

Dees C, Schlottmann I, Funke R, Distler A, Palumbo-Zerr K, Zerr P, Lin NY, Beyer C, Distler O, Schett G, Distler JH (2014) The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis. Ann Rheum Dis 73(6):1232–1239. https://doi.org/10.1136/annrheumdis-2012-203194CrossRefPubMed

145.

De Langhe E, Aznar-Lopez C, De Vooght V et al (2014) Secreted frizzled related proteins inhibit fibrosis in vitro but appear redundant in vivo. Fibrogenesis Tissue Repair 7:14. https://doi.org/10.1186/1755-1536-7-14CrossRefPubMedPubMedCentral

146.

Kohli RM, Zhang Y (2013) TET enzymes, TDG and the dynamics of DNA demethylation. Nature 502(7472):472. https://doi.org/10.1038/nature12750CrossRefPubMedPubMedCentral

147.

Hattori M et al (2015) Global DNA hypomethylation and hypoxia-induced expression of the ten eleven translocation (TET) family, TET1, in scleroderma fibroblasts. Exp Dermatol 24:841–846. https://doi.org/10.1111/exd.12767CrossRefPubMed

148.

Zhang S et al (2017) miR-30a as potential therapeutics by targeting TET1 through regulation of Drp-1 promoter hydroxymethylation in idiopathic pulmonary fibrosis. Int J Mol Sci 18(3):633. https://doi.org/10.3390/ijms18030633CrossRefPubMedCentral

149.

Evans IC, Barnes JL, Garner IM, Pearce DR, Maher TM, Shiwen X, Renzoni EA, Wells AU, Denton CP, Laurent GJ, Abraham DJ (2016) Epigenetic regulation of cyclooxygenase-2 by methylation of c8orf4 in pulmonary fibrosis. Clin Sci 130(8):575–586. https://doi.org/10.1042/CS20150697CrossRef

150.

Tharmalingam S, Sreetharan S, Kulesza AV, Boreham, Tai TC (2017) Low-dose ionizing radiation exposure, oxidative stress and epigenetic programing of health and disease. Radiat Res 188(4.2):525–538. https://doi.org/10.1667/RR14587.1CrossRefPubMed

151.

Martínez-Redondo P, Vaquero A (2013) The diversity of histone versus nonhistone sirtuin substrates. Genes Chromosomes Cancer 4(3–4):148–163. https://doi.org/10.1177/1947601913483767CrossRef

152.

Chu H, Jiang S, Liu Q, Ma Y, Zhu X, Liang M, Shi X, Ding W, Zhou X, Zou H, Qian F (2018) Sirtuin1 protects against systemic sclerosis–related pulmonary fibrosis by decreasing proinflammatory and profibrotic processes. Am J Respir Cell Mol Biol 58(1):28–39. https://doi.org/10.1165/rcmb.2016-0192OCCrossRefPubMedPubMedCentral

153.

Akamata K, Wei J, Bhattacharyya M, Cheresh P, Bonner MY, Arbiser JL, Raparia K, Gupta MP, Kamp DW, Varga J (2016) SIRT3 is attenuated in systemic sclerosis skin and lungs, and its pharmacologic activation mitigates organ fibrosis. Oncotarget 7(43):69321–69336. https://doi.org/10.18632/oncotarget.12504CrossRefPubMedPubMedCentral

154.

Sosulski ML, Gongora R, Feghali-Bostwick C, Lasky JA, Sanchez CG (2017) Sirtuin 3 deregulation promotes pulmonary fibrosis. J Gerontol A Biol Sci Med Sci 72(5):595–602. https://doi.org/10.1093/gerona/glw151CrossRefPubMed

155.

Maity S, Muhamed J, Sarikhani M, Kumar S, Ahamed F, Spurthi KM, Ravi V, Jain A, Khan D, Arathi BP, Desingu PA (2020) Sirtuin 6 deficiency transcriptionally up-regulates TGF-β signaling and induces fibrosis in mice. J Biol Chem 295(2):415–434. https://doi.org/10.1074/jbc.RA118.007212CrossRefPubMed

156.

Wyman AE, Noor Z, Fishelevich R, Lockatell V, Shah NG, Todd NW, Atamas SP (2017) Sirtuin 7 is decreased in pulmonary fibrosis and regulates the fibrotic phenotype of lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 312(6):945–958. https://doi.org/10.1152/ajplung.00473.2016CrossRef

157.

Bergmann C, Brandt A, Merlevede B, Hallenberger L, Dees C, Wohlfahrt T, Pötter S, Zhang Y, Chen CW, Mallano T, Liang R (2018) The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis. Ann Rheum Dis 77(1):150–158. https://doi.org/10.1136/annrheumdis-2017-211501CrossRefPubMed

158.

Xiao X, Senavirathna LK, Gou X, Huang C, Liang Y, Liu L (2016) EZH2 enhances the differentiation of fibroblasts into myofibroblasts in idiopathic pulmonary fibrosis. Physiol Rep 4(17):e12915. https://doi.org/10.14814/phy2.12915CrossRefPubMedPubMedCentral

159.

Pan BT, Johnstone RM (1983) Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 33:967–978CrossRefPubMed

160.

Harding C, Heuser J, Stahl P (1984) Endocytosis and intracellular processing of transferrin and colloidal gold-transferrin in rat reticulocytes: demonstration of a pathway for receptor shedding. Eur J Cell Biol 35(2):256–263PubMed

161.

Andaloussi SE, Mäger I, Breakefield XO, Wood MJ (2013) Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 12(5):347–357. https://doi.org/10.1038/nrd3978CrossRef

162.

McVey MJ, Maishan M, Blokland KE, Bartlett N, Kuebler WM (2019) Extracellular vesicles in lung health, disease, and therapy. Am J Physiol Lung Cell Mol Physiol 316(6):L977–L989. https://doi.org/10.1152/ajplung.00546.2018CrossRefPubMed

163.

Zhang Y, Liu Y, Liu H, Tang WH (2019) Exosomes: biogenesis, biologic function and clinical potential. Cell Biosci 9(1):19. https://doi.org/10.1186/s13578-019-0282-2CrossRefPubMedPubMedCentral

164.

Nomura S, Inami N, Ozaki Y, Kagawa H, Sv Fukuhara (2008) Significance of microparticles in progressive systemic sclerosis with interstitial pneumonia. Platelets 19(3):192–198. https://doi.org/10.1080/09537100701882038CrossRefPubMed

165.

Maugeri N, Capobianco A, Rovere-Querini P, Ramirez GA, Tombetti E, Della Valle P, Monno A, D’Alberti V, Gasparri AM, Franchini S, D’Angelo A (2018) Platelet microparticles sustain autophagy-associated activation of neutrophils in systemic sclerosis. Sci Transl Med 10(451):eaao3089. https://doi.org/10.1126/scitranslmed.aao3089CrossRefPubMed

166.

Lammi MR, Saketkoo LA, Okpechi SC, Ghonim MA, Wyczechowska D, Bauer N, Pyakurel K, Saito S, deBoisblanc BP, Boulares AH (2019) Microparticles in systemic sclerosis: potential pro-inflammatory mediators and pulmonary hypertension biomarkers. Respirology 24(7):675–683. https://doi.org/10.1111/resp.13500CrossRefPubMedPubMedCentral

167.

Iversen LV, Ullman S, Østergaard O, Nielsen CT, Halberg P, Karlsmark T, Heegaard NH, Jacobsen S (2015) Cross-sectional study of soluble selectins, fractions of circulating microparticles and their relationship to lung and skin involvement in systemic sclerosis. BMC Musculoskelet Disord 16(1):191. https://doi.org/10.1186/s12891-015-0653-8CrossRefPubMedPubMedCentral

168.

Takahashi T, Kobayashi S, Fujino N, Suzuki T, Ota C, Tando Y et al (2013) Differences in the released endothelial microparticle subtypes between human pulmonary microvascular endothelial cells and aortic endothelial cells in vitro. Exp Lung Res 39:155–161. https://doi.org/10.3109/01902148.2013.784932CrossRefPubMed

169.

Yao MY, Zhang WH, Ma WT, Liu QH, Xing LH, Zhao G (2019) microRNA-328 in exosomes derived from M2 macrophages exerts a promotive effect on the progression of pulmonary fibrosis via FAM13A in a rat model. Exp Mol Med 51(6):1–6. https://doi.org/10.1038/s12276-019-0255-xCrossRefPubMed

170.

Kavian N, Marut W, Servettaz A, Nicco C, Chéreau C, Lemaréchal H, Guilpain P, Chimini G, Galland F, Weill B, Naquet P (2015) Pantethine prevents murine systemic sclerosis through the inhibition of microparticle shedding. Arthritis Rheumatol 67(7):1881–1890. https://doi.org/10.1002/art.39121CrossRefPubMed

171.

Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29(4):341–345. https://doi.org/10.1038/nbt.1807CrossRefPubMed

172.

Akao Y, Iio A, Itoh T, Noguchi S, Itoh Y, Ohtsuki Y, Naoe T (2011) Microvesicle-mediated RNA molecule delivery system using monocytes/macrophages. Mol Ther 19(2):395–399. https://doi.org/10.1038/mt.2010.254CrossRefPubMed

Titel: Pulmonary involvement in systemic sclerosis: exploring cellular, genetic and epigenetic mechanisms
verfasst von: Bohdana Doskaliuk
Liubomyr Zaiats
Roman Yatsyshyn
Petro Gerych
Nataliia Cherniuk
Olena Zimba
Publikationsdatum: 26.07.2020
Verlag: Springer Berlin Heidelberg
Erschienen in: Rheumatology International / Ausgabe 10/2020
Print ISSN: 0172-8172
Elektronische ISSN: 1437-160X
DOI: https://doi.org/10.1007/s00296-020-04658-6

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So sicher sind Tattoos: Neue Daten zur Risikobewertung

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Die Highlights vom Kongress des American College of Cardiology 2024

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