{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T17:25:23Z","timestamp":1773422723658,"version":"3.50.1"},"reference-count":96,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,9,28]],"date-time":"2024-09-28T00:00:00Z","timestamp":1727481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health (NIH)","award":["R01AR073516"],"award-info":[{"award-number":["R01AR073516"]}]},{"name":"National Institutes of Health (NIH)","award":["R01AR078560"],"award-info":[{"award-number":["R01AR078560"]}]},{"name":"National Scleroderma Foundation","award":["R01AR073516"],"award-info":[{"award-number":["R01AR073516"]}]},{"name":"National Scleroderma Foundation","award":["R01AR078560"],"award-info":[{"award-number":["R01AR078560"]}]},{"name":"Nancy Taylor Foundation for Chronic Diseases","award":["R01AR073516"],"award-info":[{"award-number":["R01AR073516"]}]},{"name":"Nancy Taylor Foundation for Chronic Diseases","award":["R01AR078560"],"award-info":[{"award-number":["R01AR078560"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Localized scleroderma (LS) is an autoimmune disease characterized by inflammation and fibrosis, leading to severe cutaneous manifestations such as skin hardening, tightness, discoloration, and other textural changes that may result in disability. While LS shares similar histopathologic features and immune-fibroblast interactions with systemic sclerosis (SSc), its molecular mechanisms remain understudied. Endothelial cells (EC) are known to play a crucial role in SSc but have not been investigated in LS. Single-cell RNA sequencing (scRNA-seq) now allows for detailed examination of this cell type in the primary organ of interest for scleroderma, the skin. In this study, we analyzed skin-isolated cells from 27 LS patients (pediatric and adult) and 17 healthy controls using scRNA-seq. Given the known role of EC damage as an initial event in SSc and the histologic and clinical skin similarities to LS, we focused primarily on endothelial cells. Our analysis identified eight endothelial subclusters within the dataset, encompassing both disease and healthy samples. Interaction analysis revealed that signaling from diseased endothelial cells was predicted to promote fibrosis through SELE interaction with FGFBP1 and other target genes. We also observed high levels of JAG in arterial endothelial cells and NOTCH in capillary endothelial cells, indicating the activation of a signaling pathway potentially responsible for epidermal abnormalities and contributing to LS pathogenesis. In summary, our scRNA-seq analysis identified potential disease-propagating endothelial cell clusters with upregulated pathways in LS skin, highlighting their importance in disease progression.<\/jats:p>","DOI":"10.3390\/ijms251910473","type":"journal-article","created":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T03:12:28Z","timestamp":1727665948000},"page":"10473","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Characterization of Endothelial Cell Subclusters in Localized Scleroderma Skin with Single-Cell RNA Sequencing Identifies NOTCH Signaling Pathway"],"prefix":"10.3390","volume":"25","author":[{"given":"Theresa","family":"Hutchins","sequence":"first","affiliation":[{"name":"Department of Pediatrics (Rheumatology), University of Pittsburgh, Pittsburgh, PA 15224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7830-0949","authenticated-orcid":false,"given":"Anwesha","family":"Sanyal","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (Rheumatology), University of Pittsburgh, Pittsburgh, PA 15224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0893-0603","authenticated-orcid":false,"given":"Deren","family":"Esencan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (Rheumatology), University of Pittsburgh, Pittsburgh, PA 15224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Lafyatis","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heidi","family":"Jacobe","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Texas Southwestern, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn S.","family":"Torok","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (Rheumatology), University of Pittsburgh, Pittsburgh, PA 15224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.pcl.2018.04.002","article-title":"Scleroderma in Children and Adolescents: Localized Scleroderma and Systemic Sclerosis","volume":"65","author":"Li","year":"2018","journal-title":"Pediatr. Clin. N. Am."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Romano, E., Rosa, I., Fioretto, B.S., Matucci-Cerinic, M., and Manetti, M. (2021). New Insights into Profibrotic Myofibroblast Formation in Systemic Sclerosis: When the Vascular Wall Becomes the Enemy. Life, 11.","DOI":"10.3390\/life11070610"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1111\/bjd.17312","article-title":"Prediction of disease relapse in a cohort of paediatric patients with localized scleroderma","volume":"180","author":"Kurzinski","year":"2019","journal-title":"Br. J. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0049-0172(75)90017-7","article-title":"Pathogenesis of systemic sclerosis: A vascular hypothesis","volume":"4","author":"Campbell","year":"1975","journal-title":"Semin. Arthritis Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1002\/path.1711660307","article-title":"Sequential dermal microvascular and perivascular changes in the development of scleroderma","volume":"166","author":"Prescott","year":"1992","journal-title":"J. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1002\/art.1780261203","article-title":"Changes in vascular endothelium related to lymphocyte collections in diseased synovia","volume":"26","author":"Freemont","year":"1983","journal-title":"Arthritis Rheumatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1001\/archderm.1976.01630350029007","article-title":"Skin capillary changes in early systemic scleroderma. Electron microscopy and \u201cin vitro\u201d autoradiography with tritiated thymidine","volume":"112","author":"Fleischmajer","year":"1976","journal-title":"Arch. Dermatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1016\/j.jaad.2016.12.020","article-title":"Histopathological changes in morphea and their clinical correlates: Results from the Morphea in Adults and Children Cohort V","volume":"76","author":"Walker","year":"2017","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1002\/art.1780270607","article-title":"Lymphocytes in the skin of patients with progressive systemic sclerosis. Quantification, subtyping, and clinical correlations","volume":"27","author":"Roumm","year":"1984","journal-title":"Arthritis Rheumatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1097\/00002281-200211000-00010","article-title":"Targeting mediators of vascular injury in scleroderma","volume":"14","author":"Schachna","year":"2002","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1002\/art.37712","article-title":"Differential expression of junctional adhesion molecules in different stages of systemic sclerosis","volume":"65","author":"Manetti","year":"2013","journal-title":"Arthritis Rheumatol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Lunardi, C., Dolcino, M., Peterlana, D., Bason, C., Navone, R., Tamassia, N., Beri, R., Corrocher, R., and Puccetti, A. (2006). Antibodies against human cytomegalovirus in the pathogenesis of systemic sclerosis: A gene array approach. PLoS Med., 3.","DOI":"10.1371\/journal.pmed.0030002"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1136\/annrheumdis-2011-200713","article-title":"Quantification of circulating endothelial progenitor cells in systemic sclerosis: A direct comparison of protocols","volume":"71","author":"Kuwana","year":"2012","journal-title":"Ann. Rheum. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1002\/art.20116","article-title":"Circulating endothelial cells as a marker of ongoing vascular disease in systemic sclerosis","volume":"50","author":"Colombo","year":"2004","journal-title":"Arthritis Rheumatol."},{"key":"ref_15","first-page":"1325","article-title":"Mechanisms of endothelial cell damage in systemic sclerosis and Raynaud\u2019s phenomenon","volume":"20","author":"Blann","year":"1993","journal-title":"J. Rheumatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.cyto.2011.04.001","article-title":"Cytokine profiles in localized scleroderma and relationship to clinical features","volume":"55","author":"Kurzinski","year":"2011","journal-title":"Cytokine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3004","DOI":"10.1002\/art.39287","article-title":"A longitudinal biomarker for the extent of skin disease in patients with diffuse cutaneous systemic sclerosis","volume":"67","author":"Rice","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1097\/00002281-200311000-00012","article-title":"Fibroblast and endothelial apoptosis in systemic sclerosis","volume":"15","author":"Jun","year":"2003","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Apostolidis, S.A., Stifano, G., Tabib, T., Rice, L.M., Morse, C.M., Kahaleh, B., and Lafyatis, R. (2018). Single Cell RNA Sequencing Identifies HSPG2 and APLNR as Markers of Endothelial Cell Injury in Systemic Sclerosis Skin. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02191"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1002\/art.37988","article-title":"Review: Evidence that systemic sclerosis is a vascular disease","volume":"65","author":"Kahaleh","year":"2013","journal-title":"Arthritis Rheumatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3117","DOI":"10.1182\/blood-2009-02-203372","article-title":"Interleukin-33 induces angiogenesis and vascular permeability through ST2\/TRAF6-mediated endothelial nitric oxide production","volume":"114","author":"Choi","year":"2009","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.autrev.2017.05.024","article-title":"The role of endothelial cells in the vasculopathy of systemic sclerosis: A systematic review","volume":"16","author":"Mostmans","year":"2017","journal-title":"Autoimmun. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s10875-014-0037-0","article-title":"Early systemic sclerosis: Serum profiling of factors involved in endothelial, T-cell, and fibroblast interplay is marked by elevated interleukin-33 levels","volume":"34","author":"Vettori","year":"2014","journal-title":"J. Clin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1136\/ard.2010.148247","article-title":"Increased circulating levels of interleukin 33 in systemic sclerosis correlate with early disease stage and microvascular involvement","volume":"70","author":"Manetti","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1136\/annrheumdis-2012-201553","article-title":"Increased serum IL-33 levels may indicate vascular involvement in systemic sclerosis","volume":"72","author":"Terras","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Song, M., Wang, Y., Annex, B.H., and Popel, A.S. (2023). Experiment-based Computational Model Predicts that IL-6 Trans-Signaling Plays a Dominant Role in IL-6 mediated signaling in Endothelial Cells. bioRxiv.","DOI":"10.1101\/2023.02.03.526721"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"777","DOI":"10.3892\/ijmm.2014.1657","article-title":"Inflammation and peripheral arterial disease: The value of circulating biomarkers (Review)","volume":"33","author":"Signorelli","year":"2014","journal-title":"Int. J. Mol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1038\/nri2171","article-title":"Evolving functions of endothelial cells in inflammation","volume":"7","author":"Pober","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1186\/s13075-020-02343-4","article-title":"Single-cell transcriptome conservation in a comparative analysis of fresh and cryopreserved human skin tissue: Pilot in localized scleroderma","volume":"22","author":"Mirizio","year":"2020","journal-title":"Arthritis Res. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Werner, G., Sanyal, A., Mirizio, E., Hutchins, T., Tabib, T., Lafyatis, R., Jacobe, H., and Torok, K.S. (2023). Single-Cell Transcriptome Analysis Identifies Subclusters with Inflammatory Fibroblast Responses in Localized Scleroderma. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24129796"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Rojas, M.G., Zigmond, Z.M., Pereira-Simon, S., Falcon, N.S., Kumar, M.S., Stoyell-Conti, F.F., Kosanovic, C., Griswold, A.J., Salama, A., and Yang, X. (2024). The intricate cellular ecosystem of human peripheral veins as revealed by single-cell transcriptomic analysis. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0296264"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Vaahtomeri, K., Moussion, C., Hauschild, R., and Sixt, M. (2021). Shape and Function of Interstitial Chemokine CCL21 Gradients Are Independent of Heparan Sulfates Produced by Lymphatic Endothelium. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.630002"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s00441-023-03741-1","article-title":"The role of PLVAP in endothelial cells","volume":"392","author":"Denzer","year":"2023","journal-title":"Cell Tissue Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/sj.jid.5700101","article-title":"Numerous keratinocyte subtypes involved in wound re-epithelialization","volume":"126","author":"Patel","year":"2006","journal-title":"J. Investig. Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Zhu, K., Cai, L., Cui, C., de Los Toyos, J.R., and Anastassiou, D. (2021). Single-cell analysis reveals the pan-cancer invasiveness-associated transition of adipose-derived stromal cells into COL11A1-expressing cancer-associated fibroblasts. PLoS Comput. Biol., 17.","DOI":"10.1371\/journal.pcbi.1009228"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41467-021-27801-8","article-title":"Single cell transcriptomic landscape of diabetic foot ulcers","volume":"13","author":"Theocharidis","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Sun, J., Qiao, Y.-N., Tao, T., Zhao, W., Wei, L.-S., Li, Y.-Q., Wang, W., Wang, Y., Zhou, Y.-W., and Zheng, Y.-Y. (2020). Distinct Roles of Smooth Muscle and Non-muscle Myosin Light Chain-Mediated Smooth Muscle Contraction. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.593966"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Hadadi, E., Zhang, B., Baid\u017eajevas, K., Yusof, N., Puan, K.J., Ong, S.M., Yeap, W.H., Rotzschke, O., Kiss-Toth, E., and Wilson, H. (2016). Differential IL-1beta secretion by monocyte subsets is regulated by Hsp27 through modulating mRNA stability. Sci. Rep., 6.","DOI":"10.1038\/srep39035"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2352","DOI":"10.1089\/ars.2012.4834","article-title":"CD163 and inflammation: Biological, diagnostic, and therapeutic aspects","volume":"18","author":"Etzerodt","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Nikovics, K., and Favier, A.L. (2021). Macrophage Identification In Situ. Biomedicines, 9.","DOI":"10.3390\/biomedicines9101393"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1908010","DOI":"10.1080\/2162402X.2021.1908010","article-title":"Investigating Mechanisms of Response or Resistance to Immune Checkpoint Inhibitors by Analyzing Cell-Cell Communications in Tumors Before and After Programmed Cell Death-1 (PD-1) Targeted Therapy: An Integrative Analysis Using Single-cell RNA and Bulk-RNA Sequencing Data","volume":"10","author":"Jiang","year":"2021","journal-title":"Oncoimmunology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.ajpath.2015.10.030","article-title":"Anti-Inflammatory Action of Keratinocyte-Derived Vaspin: Relevance for the Pathogenesis of Psoriasis","volume":"186","author":"Saalbach","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1113\/jphysiol.2001.020180","article-title":"Localization of aquaporin-5 in sweat glands and functional analysis using knockout mice","volume":"541","author":"Song","year":"2002","journal-title":"J. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1007\/s12264-017-0147-9","article-title":"Somatosensory Neuron Typing with High-Coverage Single-Cell RNA Sequencing and Functional Analysis","volume":"34","author":"Li","year":"2018","journal-title":"Neurosci. Bull."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Tkachenko, A., Kupcova, K., and Havranek, O. (2023). B-Cell Receptor Signaling and Beyond: The Role of Igalpha (CD79a)\/Igbeta (CD79b) in Normal and Malignant B Cells. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010010"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.2337\/db20-0188","article-title":"Integrated Skin Transcriptomics and Serum Multiplex Assays Reveal Novel Mechanisms of Wound Healing in Diabetic Foot Ulcers","volume":"69","author":"Theocharidis","year":"2020","journal-title":"Diabetes"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"He, Y., Tacconi, C., Dieterich, L.C., Kim, J., Restivo, G., Gousopoulos, E., Lindenblatt, N., Levesque, M.P., Claassen, M., and Detmar, M. (2022). Novel Blood Vascular Endothelial Subtype-Specific Markers in Human Skin Unearthed by Single-Cell Transcriptomic Profiling. Cells, 11.","DOI":"10.3390\/cells11071111"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Huang, M., Tabib, T., Khanna, D., Assassi, S., Domsic, R., and Lafyatis, R. (2024). Single-cell transcriptomes and chromatin accessibility of endothelial cells unravel transcription factors associated with dysregulated angiogenesis in systemic sclerosis. Ann. Rheum. Dis., online ahead of print.","DOI":"10.1136\/ard-2023-225415"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2905","DOI":"10.3892\/or.2017.5565","article-title":"Differential effects of sulforaphane in regulation of angiogenesis in a co-culture model of endothelial cells and pericytes","volume":"37","author":"Wang","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"23436","DOI":"10.1074\/jbc.M109.032664","article-title":"RGS5, a hypoxia-inducible apoptotic stimulator in endothelial cells","volume":"284","author":"Jin","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"6863","DOI":"10.3390\/ijms14046863","article-title":"Impact of notch signaling on inflammatory responses in cardiovascular disorders","volume":"14","author":"Quillard","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Zahoor, M.A., Xue, G., Sato, H., Murakami, T., Takeshima, S.-N., and Aida, Y. (2014). HIV-1 Vpr induces interferon-stimulated genes in human monocyte-derived macrophages. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0106418"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Gratton, R., Tricarico, P.M., Pio d, A., Bianco, A.M., Moura, R., Agrelli, A., Brand\u00e3o, L., Zupin, L., and Crovella, S. (2020). Notch Signaling Regulation in Autoinflammatory Diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228847"},{"key":"ref_54","first-page":"543","article-title":"E-selectin and intercellular adhesion molecule-1 are released by activated human endothelial cells in vitro","volume":"77","author":"Leeuwenberg","year":"1992","journal-title":"Immunology"},{"key":"ref_55","first-page":"153","article-title":"Mice lacking E-selectin show normal numbers of rolling leukocytes but reduced leukocyte stable arrest on cytokine-activated microvascular endothelium","volume":"5","author":"Milstone","year":"1998","journal-title":"Microcirculation"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3009","DOI":"10.1182\/blood.V89.8.3009","article-title":"Differential effect of E-selectin antibodies on neutrophil rolling and recruitment to inflammatory sites","volume":"89","author":"Ramos","year":"1997","journal-title":"Blood"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3301","DOI":"10.4049\/jimmunol.164.6.3301","article-title":"Leukocyte arrest during cytokine-dependent inflammation in vivo","volume":"164","author":"Kunkel","year":"2000","journal-title":"J. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1161\/01.RES.83.3.287","article-title":"Importance of E-selectin for firm leukocyte adhesion in vivo","volume":"83","author":"Ley","year":"1998","journal-title":"Circ Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2570","DOI":"10.7150\/ijms.45408","article-title":"Down-regulation of Xist and Mir-7a-5p improves LPS-induced myocardial injury","volume":"17","author":"Liang","year":"2020","journal-title":"Int. J. Med. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.cell.2023.12.037","article-title":"Xist ribonucleoproteins promote female sex-biased autoimmunity","volume":"187","author":"Dou","year":"2024","journal-title":"Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"155891","DOI":"10.1016\/j.cyto.2022.155891","article-title":"Interleukin-33 (IL-33): A critical review of its biology and the mechanisms involved in its release as a potent extracellular cytokine","volume":"156","author":"Cayrol","year":"2022","journal-title":"Cytokine"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Hasegawa, T., Oka, T., and Demehri, S. (2022). Alarmin Cytokines as Central Regulators of Cutaneous Immunity. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.876515"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/cmi.2016.34","article-title":"HMGB1, IL-1alpha, IL-33 and S100 proteins: Dual-function alarmins","volume":"14","author":"Bertheloot","year":"2017","journal-title":"Cell Mol. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Pendergrass, S.A., Hayes, E., Farina, G., Lemaire, R., Farber, H.W., Whitfield, M.L., and Lafyatis, R. (2010). Limited systemic sclerosis patients with pulmonary arterial hypertension show biomarkers of inflammation and vascular injury. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012106"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1002\/art.41265","article-title":"The Utility of Plasma Vascular Biomarkers in Systemic Sclerosis: A Prospective Longitudinal Analysis","volume":"72","author":"Mecoli","year":"2020","journal-title":"Arthritis Rheumatol."},{"key":"ref_66","first-page":"102","article-title":"Prediction of organ involvement in systemic sclerosis by serum biomarkers and peripheral endothelial function","volume":"36","author":"Kawashiri","year":"2018","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1016\/j.cell.2022.03.011","article-title":"LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma","volume":"185","author":"Gur","year":"2022","journal-title":"Cell"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.jid.2018.09.025","article-title":"Identifying the Signature Immune Phenotypes Present in Pediatric Localized Scleroderma","volume":"139","author":"Mirizio","year":"2019","journal-title":"J. Investig. Dermatol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1016\/j.jid.2017.04.008","article-title":"Transcriptional and Cytokine Profiles Identify CXCL9 as a Biomarker of Disease Activity in Morphea","volume":"137","author":"Rainwater","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Spasovski, V., Andjelkovic, M., Parezanovic, M., Komazec, J., Ugrin, M., Klaassen, K., and Stojiljkovic, M. (2023). The Role of Autophagy and Apoptosis in Affected Skin and Lungs in Patients with Systemic Sclerosis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241311212"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1242\/dev.01074","article-title":"Notch signaling: Control of cell communication and cell fate","volume":"131","author":"Lai","year":"2004","journal-title":"Development"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1165\/rcmb.2012-0262OC","article-title":"Reversal of myofibroblast differentiation by prostaglandin E(2)","volume":"48","author":"Garrison","year":"2013","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1136\/ard.2010.134742","article-title":"Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis","volume":"70","author":"Dees","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"774","DOI":"10.3904\/kjim.2016.230","article-title":"Notch signaling in the collecting duct regulates renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction in mice","volume":"33","author":"Choi","year":"2018","journal-title":"Korean J. Intern. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1111\/exd.12673","article-title":"Current frontiers in systemic sclerosis pathogenesis","volume":"24","author":"Ciechomska","year":"2015","journal-title":"Exp. Dermatol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/S0092-8674(04)00451-9","article-title":"Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells","volume":"117","author":"Amsen","year":"2004","journal-title":"Cell"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"4040","DOI":"10.1172\/JCI43025","article-title":"Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans","volume":"120","author":"Bielesz","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1038\/s41467-020-15817-5","article-title":"Endothelial E-selectin inhibition improves acute myeloid leukaemia therapy by disrupting vascular niche-mediated chemoresistance","volume":"11","author":"Barbier","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s00408-015-9718-6","article-title":"In situ evidence of pulmonary endothelial activation in patients with granulomatosis with polyangiitis and systemic sclerosis","volume":"193","author":"Ab","year":"2015","journal-title":"Lung"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Mouawad, J.E., and Feghali-Bostwick, C. (2023). The Molecular Mechanisms of Systemic Sclerosis-Associated Lung Fibrosis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032963"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1007\/s10067-011-1686-5","article-title":"Serum IL-33 levels are raised in patients with systemic sclerosis: Association with extent of skin sclerosis and severity of pulmonary fibrosis","volume":"30","author":"Yanaba","year":"2011","journal-title":"Clin. Rheumatol."},{"key":"ref_82","first-page":"1156","article-title":"Combined inhibition of IL-1, IL-33 and IL-36 signalling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of systemic sclerosis","volume":"2024. 83","author":"Rattik","year":"2024","journal-title":"Ann. Rheum. Dis."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"England, E., Rees, D.G., Scott, I.C., Carmen, S., Chan, D.T.Y., Huntington, C.E.C., Houslay, K.F., Erngren, T., Penney, M., and Majithiy, J.B. (2023). Tozorakimab (MEDI3506): An anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE\/EGFR to reduce inflammation and epithelial dysfunction. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-36642-y"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1164\/rccm.202103-0714OC","article-title":"Long-Term Safety and Efficacy of Tocilizumab in Early Systemic Sclerosis-Interstitial Lung Disease: Open-Label Extension of a Phase 3 Randomized Controlled Trial","volume":"205","author":"Khanna","year":"2022","journal-title":"Am. J. Respir. Crit Care Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"5405","DOI":"10.7150\/ijbs.75876","article-title":"The Role of IL-6 in Fibrotic Diseases: Molecular and Cellular Mechanisms","volume":"18","author":"Li","year":"2022","journal-title":"Int. J. Biol. Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1093\/rheumatology\/34.2.101","article-title":"The role of IL-4 and IL-6 in IL-1-dependent cartilage matrix degradation","volume":"34","author":"Shingu","year":"1995","journal-title":"Br. J. Rheumatol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1038\/s41577-023-00856-y","article-title":"Targeting IL-6 trans-signalling: Past, present and future prospects","volume":"23","author":"Jenkins","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.1038\/cti.2013.2","article-title":"Interleukin-6: A new therapeutic target in systemic sclerosis?","volume":"2","author":"Cant","year":"2013","journal-title":"Clin. Transl. Immunol."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Jin, J., Liu, Y., Tang, Q., Yan, X., Jiang, M., Zhao, X., Chen, J., Jin, C., Ou, Q., and Zhao, J. (2023). Bioinformatics-integrated screening of systemic sclerosis-specific expressed markers to identify therapeutic targets. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1125183"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"154944","DOI":"10.1016\/j.prp.2023.154944","article-title":"Unraveling the role of Xist RNA in cardiovascular pathogenesis","volume":"253","author":"Almalki","year":"2024","journal-title":"Pathol. Res. Pract."},{"key":"ref_91","first-page":"6487","article-title":"Long noncoding RNA XIST participates hypoxia-induced angiogenesis in human brain microvascular endothelial cells through regulating miR-485\/SOX7 axis","volume":"11","author":"Hu","year":"2019","journal-title":"Am. J. Transl. Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.omtn.2021.06.025","article-title":"Silencing of lncRNA XIST impairs angiogenesis and exacerbates cerebral vascular injury after ischemic stroke","volume":"26","author":"Wang","year":"2021","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"7729","DOI":"10.1038\/s41467-022-35319-w","article-title":"Spatial transcriptomics landscape of lesions from non-communicable inflammatory skin diseases","volume":"13","author":"Hillig","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"5692","DOI":"10.1038\/s41467-021-25960-2","article-title":"Confronting false discoveries in single-cell differential expression","volume":"12","author":"Squair","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/s41592-019-0667-5","article-title":"NicheNet: Modeling intercellular communication by linking ligands to target genes","volume":"17","author":"Browaeys","year":"2020","journal-title":"Nat. Methods"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"Jin","year":"2021","journal-title":"Nat. Commun."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/19\/10473\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:06:03Z","timestamp":1760112363000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/19\/10473"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,28]]},"references-count":96,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["ijms251910473"],"URL":"https:\/\/doi.org\/10.3390\/ijms251910473","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,28]]}}}