{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:07:07Z","timestamp":1792789627187,"version":"4.5.0"},"reference-count":37,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"RIFCI","award":["124112200103-3"],"award-info":[{"award-number":["124112200103-3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dendritic cells (DCs) play a central role in the immunopathogenesis of rheumatoid arthritis (RA), yet their regulation by tumor necrosis factor alpha (TNF) and associated receptors remains poorly characterized. We applied a single-cell multi-omics approach (CITE-seq) to profile peripheral blood mononuclear cells (PBMCs) from RA patients and healthy donors, before and after in vitro TNF stimulation. Using integrated analysis of surface protein expression and transcriptomic data, we focused on phenotypic and transcriptional changes in dendritic cell populations. DCs from RA patients exhibited elevated surface expression of CD14 and CD16, indicative of an inflammatory phenotype, and showed marked responsiveness to TNF. Upon stimulation, RA-derived DCs upregulated genes involved in antigen presentation (CD83, LAMP3), lymph node migration (CCR7, ADAM19), and inflammation (TRAF1, IL24) whereas such activation was absent in healthy controls. Our data reveal a TNF-responsive, pro-inflammatory transcriptional program in dendritic cells from RA patients and underscore the relevance of the TNF receptor profile in shaping DC function. These findings provide new insights into the immunobiology of RA and identify dendritic cells as potential targets for personalized immunomodulatory therapy.<\/jats:p>","DOI":"10.3390\/ijms26136071","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T12:05:40Z","timestamp":1750766740000},"page":"6071","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Molecular Signatures of Dendritic Cell Activation upon TNF Stimulation: A Multi-Omics Study in Rheumatoid Arthritis"],"prefix":"10.3390","volume":"26","author":[{"given":"Alina","family":"Alshevskaya","sequence":"first","affiliation":[{"name":"Laboratory of Immune Engineering, Federal State Autonomous Educational Institution of Higher Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 119048 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8951-9727","authenticated-orcid":false,"given":"Shakir","family":"Suleimanov","sequence":"additional","affiliation":[{"name":"Laboratory of Immune Engineering, Federal State Autonomous Educational Institution of Higher Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 119048 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0927-5735","authenticated-orcid":false,"given":"Elizaveta","family":"Sheveleva","sequence":"additional","affiliation":[{"name":"Laboratory of Immune Engineering, Federal State Autonomous Educational Institution of Higher Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 119048 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5055-4859","authenticated-orcid":false,"given":"Roman","family":"Perik-Zavodskii","sequence":"additional","affiliation":[{"name":"Laboratory of Immune Engineering, Federal State Autonomous Educational Institution of Higher Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 119048 Moscow, Russia"},{"name":"Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology (RIFCI), 630099 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4911-1994","authenticated-orcid":false,"given":"Olga","family":"Perik-Zavodskaia","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology (RIFCI), 630099 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0788-5385","authenticated-orcid":false,"given":"Saleh","family":"Alrhmoun","sequence":"additional","affiliation":[{"name":"Laboratory of Immune Engineering, Federal State Autonomous Educational Institution of Higher Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 119048 Moscow, Russia"},{"name":"Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology (RIFCI), 630099 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0089-5054","authenticated-orcid":false,"given":"Julia","family":"Lopatnikova","sequence":"additional","affiliation":[{"name":"Laboratory of Immune Engineering, Federal State Autonomous Educational Institution of Higher Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 119048 Moscow, Russia"},{"name":"Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology (RIFCI), 630099 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2287-0918","authenticated-orcid":false,"given":"Julia","family":"Zhukova","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology (RIFCI), 630099 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadezhda","family":"Shkaruba","sequence":"additional","affiliation":[{"name":"Rheumatology Department of the Immunopathology Clinic, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Sivitskaya","sequence":"additional","affiliation":[{"name":"Laboratory of Immune Engineering, Federal State Autonomous Educational Institution of Higher Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 119048 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey","family":"Sizikov","sequence":"additional","affiliation":[{"name":"Rheumatology Department of the Immunopathology Clinic, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Golikova","sequence":"additional","affiliation":[{"name":"Laboratory of Immune Engineering, Federal State Autonomous Educational Institution of Higher Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 119048 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7366-7768","authenticated-orcid":false,"given":"Sergey","family":"Sennikov","sequence":"additional","affiliation":[{"name":"Laboratory of Immune Engineering, Federal State Autonomous Educational Institution of Higher Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 119048 Moscow, Russia"},{"name":"Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology (RIFCI), 630099 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1186\/ar2200","article-title":"Cells of the synovium in rheumatoid arthritis. Dendritic cells","volume":"9","author":"Lutzky","year":"2007","journal-title":"Arthritis Res. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Suwa, Y., Nagafuchi, Y., Yamada, S., and Fujio, K. (2023). The role of dendritic cells and their immunometabolism in rheumatoid arthritis. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1161148"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/cei.13256","article-title":"Dendritic cells, T cells and their interaction in rheumatoid arthritis","volume":"196","author":"Wehr","year":"2019","journal-title":"Clin. Exp. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1001\/archderm.140.2.218","article-title":"Potential of tumor necrosis factor inhibitors in psoriasis and psoriatic arthritis","volume":"140","author":"Krueger","year":"2004","journal-title":"Arch. Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1517\/13543784.12.7.1087","article-title":"The therapeutic potential of TNF-alpha blockade in rheumatoid arthritis","volume":"12","author":"Paleolog","year":"2003","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1007\/s40265-014-0239-z","article-title":"Certolizumab pegol: A review of its use in patients with axial spondyloarthritis or psoriatic arthritis","volume":"74","author":"Dhillon","year":"2014","journal-title":"Drugs"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"156136","DOI":"10.1016\/j.cyto.2023.156136","article-title":"Majoon chobchini reinstates PDL-1 expression and blocks dendritic cell\u2013T helper 17 pathogenic axis in rheumatoid arthritis animal model","volume":"163","author":"Samarpita","year":"2023","journal-title":"Cytokine"},{"key":"ref_8","first-page":"291","article-title":"Role subpopulation of dendritic cells in the pathogenesis of rheumatoid arthritis","volume":"35","author":"Falaleeva","year":"2014","journal-title":"Immunologiya"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.humimm.2009.02.006","article-title":"Dendritic cells in rheumatoid arthritis: Which subset should be used as a tool to induce tolerance?","volume":"70","author":"Lebre","year":"2009","journal-title":"Hum. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1002\/art.25037","article-title":"Novel role of plasmacytoid dendritic cells in humans: Induction of interleukin-10-producing Treg cells in patients with rheumatoid arthritis responding to therapy","volume":"62","author":"Kavousanaki","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ning, B., Wei, J., Zhang, A., Gong, W., Fu, J., Jia, T., and You-Yang, S. (2015). Antigen-specific tolerogenic dendritic cells ameliorate the severity of murine collagen-induced arthritis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0131152"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.cyto.2016.08.027","article-title":"TNFR signalling and its clinical implications","volume":"101","author":"Tseng","year":"2018","journal-title":"Cytokine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"23","DOI":"10.2165\/00063030-200721010-00004","article-title":"Tumor necrosis factor receptor pre-ligand assembly domain is an important therapeutic target in inflammatory arthritis","volume":"21","author":"Deng","year":"2007","journal-title":"BioDrugs"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1136\/ard.2004.023259","article-title":"Inhibition of TNF alpha during maturation of dendritic cells results in the development of semi-mature cells","volume":"64","author":"Barrera","year":"2005","journal-title":"Ann. Rheum. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ye, L.L., Wei, X.S., Zhang, M., Niu, Y.R., and Zhou, Q. (2018). The significance of tumor necrosis factor receptor type II in CD8+ regulatory T cells and CD8+ effector T cells. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00583"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5024","DOI":"10.4049\/jimmunol.175.8.5024","article-title":"Paradoxical anti-inflammatory actions of TNF-alpha via TNF receptor 1 in macrophages and dendritic cells","volume":"175","author":"Zakharova","year":"2005","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"111","DOI":"10.12688\/f1000research.17023.1","article-title":"Tumour necrosis factor signalling in health and disease","volume":"8","author":"Holbrook","year":"2019","journal-title":"F1000Research"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Alshevskaya, A., Lopatnikova, J., Zhukova, J., Chumasova, O., Shkaruba, N., Sizikov, A., Evsegneeva, I., Gladkikh, V., Karaulov, A., and Sennikov, S.V. (2019). Co-expression profile of TNF membrane-bound receptors type 1 and 2 in rheumatoid arthritis on immunocompetent cells subsets. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010288"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1002\/art.40793","article-title":"Association of dendritic cell signatures with autoimmune inflammation revealed by single-cell profiling","volume":"71","author":"Ashton","year":"2019","journal-title":"Arthritis Rheumatol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Figueiredo, M.L. (2024). Applications of single-cell RNA sequencing in rheumatoid arthritis. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1491318"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e008983","DOI":"10.1136\/jitc-2024-008983","article-title":"Interactions between LAMP3+ dendritic cells and T-cell subpopulations promote immune evasion in papillary thyroid carcinoma","volume":"12","author":"Wang","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Grosche, L., Knippertz, I., K\u00f6nig, C., Royzman, D., Wild, A.B., Zinser, E., Sticht, H., Muller, Y.A., Steinkasserer, A., and Lechmann, M. (2020). The CD83 molecule\u2014An important immune checkpoint. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00721"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1038\/nri2297","article-title":"CCR7 and its ligands: Balancing immunity and tolerance","volume":"8","author":"Rot","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zhong, Y., Zhang, X., and Chong, W. (2022). Interleukin-24 immunobiology and its roles in inflammatory diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020627"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Edilova, M.I., Abdul-Sater, A.A., and Watts, T.H. (2018). TRAF1 signaling in human health and disease. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02969"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"103377","DOI":"10.1016\/j.jaut.2025.103377","article-title":"Selective disruption of Traf1\/cIAP2 interaction attenuates inflammatory responses and rheumatoid arthritis","volume":"152","author":"Tang","year":"2025","journal-title":"J. Autoimmun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1096\/fj.08-119040","article-title":"Annexin-1-deficient dendritic cells acquire a mature phenotype during differentiation","volume":"23","author":"Huggins","year":"2009","journal-title":"FASEB J."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Pieper, D., Schirmer, S., Prechtel, A.T., Kehlenbach, R.H., Hauber, J., and Chemnitz, J. (2011). Functional characterization of the HuR:CD83 mRNA interaction. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023290"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"152","DOI":"10.4049\/jimmunol.171.1.152","article-title":"Dendritic cells support sequential reprogramming of chemoattractant receptor profiles during naive to effector T cell differentiation","volume":"171","author":"Kim","year":"2003","journal-title":"J. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1615\/CritRevImmunol.2018026790","article-title":"Immunomodulatory bonds of the partnership between dendritic cells and T cells","volume":"38","author":"Bourque","year":"2018","journal-title":"Crit. Rev. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.immuni.2019.08.008","article-title":"Single-cell analysis of human mononuclear phagocytes reveals subset-defining markers and identifies circulating inflammatory dendritic cells","volume":"51","author":"Dutertre","year":"2019","journal-title":"Immunity"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1016\/j.ccell.2024.06.009","article-title":"Spatiotemporal single-cell analysis decodes cellular dynamics underlying different responses to immunotherapy in colorectal cancer","volume":"42","author":"Chen","year":"2024","journal-title":"Cancer Cell"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Wolf, F.A., Angerer, P., and Theis, F.J. (2018). SCANPY: Large-scale single-cell gene expression data analysis. Genome Biol., 19.","DOI":"10.1186\/s13059-017-1382-0"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.cels.2018.11.005","article-title":"Scrublet: Computational identification of cell doublets in single-cell transcriptomic data","volume":"8","author":"Wolock","year":"2019","journal-title":"Cell Syst."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","article-title":"Fast, sensitive and accurate integration of single-cell data with Harmony","volume":"16","author":"Korsunsky","year":"2019","journal-title":"Nat. Methods"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Anders, S., and Huber, W. (2010). Differential expression analysis for sequence count data. Genome Biol., 11.","DOI":"10.1186\/gb-2010-11-10-r106"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6071\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:57:59Z","timestamp":1760032679000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6071"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,24]]},"references-count":37,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26136071"],"URL":"https:\/\/doi.org\/10.3390\/ijms26136071","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,24]]}}}