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Hiroshima","award":["19K18499"],"award-info":[{"award-number":["19K18499"]}]},{"name":"Rotary Club of Hiroshima","award":["22K08599"],"award-info":[{"award-number":["22K08599"]}]},{"name":"Rotary Club of Hiroshima","award":["JP21fk0108558"],"award-info":[{"award-number":["JP21fk0108558"]}]},{"name":"Rotary Club of Hiroshima","award":["JP21fk0108550"],"award-info":[{"award-number":["JP21fk0108550"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), utilizes the host receptor angiotensin-converting enzyme 2 (ACE2) and the auxiliary receptor Neuropilin-1 (NRP1) to enter host cells. NRP1 has another isoform, NRP2, whose function in COVID-19 has seldom been reported. In addition, although patients with severe cases of COVID-19 often exhibit increased levels of proinflammatory cytokines, the relationship between these cytokines and SARS-CoV-2 proliferation remains unknown. The aim of this study is to clarify the roles of proinflammatory cytokines in Neuropilin expressions and in SARS-CoV-2 infection. To identify the expression patterns of NRP under inflamed and noninflamed conditions, next-generation sequencing (RNA-seq), immunohistochemistry, quantitative real-time PCR, and Western blotting were performed using primary cultured fibroblast-like synoviocytes, MH7A (immortalized cell line of human rheumatoid fibroblast-like synoviocytes), immortalized MRC5 (human embryonic lung fibroblast), and synovial tissues. To measure viral proliferative capacity, SARS-CoV-2 infection experiments were also performed. NRP2 was upregulated in inflamed tissues. Cytokine-stimulated human fibroblast cell lines, such as MH7A and immortalized MRC5, revealed that NRP2 expression increased with co-stimulation of tumor necrosis factor \u03b1 (TNF\u03b1) and interleukin-1 beta (IL-1\u03b2) and was suppressed with anti-TNF\u03b1 antibody alone. TNF\u03b1 and IL-1\u03b2 promoted SARS-CoV-2 proliferation and Spike protein binding. The viral proliferation coincided with the expression of NRP2, which was modulated through plasmid transfections. Our results revealed that proinflammatory cytokines, including TNF\u03b1, contribute to NRP2 upregulation and SARS-CoV-2 proliferation in host human cells.<\/jats:p>","DOI":"10.3390\/v15071498","type":"journal-article","created":{"date-parts":[[2023,7,4]],"date-time":"2023-07-04T01:32:18Z","timestamp":1688434338000},"page":"1498","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Tumor Necrosis Factor and Interleukin-1\u03b2 Upregulate NRP2 Expression and Promote SARS-CoV-2 Proliferation"],"prefix":"10.3390","volume":"15","author":[{"given":"Michinori","family":"Ishitoku","sequence":"first","affiliation":[{"name":"Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima 734-8551, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8529-1016","authenticated-orcid":false,"given":"Sho","family":"Mokuda","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima 734-8551, Japan"},{"name":"Division of Laboratory Medicine, Hiroshima University Hospital, Hiroshima 734-8551, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Araki","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima 734-8551, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima 734-8551, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2947-6216","authenticated-orcid":false,"given":"Hiroki","family":"Kohno","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima 734-8551, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Sugimoto","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima 734-8551, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima 734-8551, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3754-1252","authenticated-orcid":false,"given":"Takemasa","family":"Sakaguchi","sequence":"additional","affiliation":[{"name":"Department of Virology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0847-0456","authenticated-orcid":false,"given":"Junya","family":"Masumoto","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ehime University Proteo-Science Center and Graduate School of Medicine, Toon 791-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shintaro","family":"Hirata","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima 734-8551, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiji","family":"Sugiyama","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima 734-8551, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1056\/NEJMoa2001316","article-title":"Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus\u2013Infected Pneumonia","volume":"382","author":"Li","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1001\/jama.2020.2648","article-title":"Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72,314 Cases from the Chinese Center for Disease Control and Prevention","volume":"323","author":"Wu","year":"2020","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1056\/NEJMoa2034577","article-title":"Clinical Trial Group. Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine","volume":"383","author":"Polack","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1056\/NEJMoa2031994","article-title":"ACTT-2 Study Group Members. Baricitinib plus Remdesivir for Hospitalized Adults with COVID-19","volume":"384","author":"Kalil","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1056\/NEJMc2119407","article-title":"Efficacy of Antibodies and Antiviral Drugs Against COVID-19 Omicron Variant","volume":"386","author":"Takashita","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/path.1570","article-title":"Tissue Distribution of ACE2 Protein, the Functional Receptor for SARS Coronavirus. A First Step in Understanding SARS Pathogenesis","volume":"203","author":"Hamming","year":"2004","journal-title":"J. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Bestle, D., Heindl, M.R., Limburg, H., Van Lam Van, T., Pilgram, O., Moulton, H., Stein, D.A., Hardes, K., Eickmann, M., and Dolnik, O. (2020). TMPRSS2 and Furin Are Both Essential for Proteolytic Activation of SARS-CoV-2 in Human Airway Cells. Life Sci. Alliance, 3.","DOI":"10.1101\/2020.04.15.042085"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1038\/nri3545","article-title":"Immunological Functions of the Neuropilins and Plexins as Receptors for Semaphorins","volume":"13","author":"Kumanogoh","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1126\/science.abd3072","article-title":"Neuropilin-1 Is a Host Factor for SARS-CoV-2 Infection","volume":"370","author":"Daly","year":"2020","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1038\/s41591-020-1051-9","article-title":"An Inflammatory Cytokine Signature Predicts COVID-19 Severity and Survival","volume":"26","author":"Huang","year":"2020","journal-title":"Nat. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1002\/jmv.26232","article-title":"The Cytokine Storm and COVID-19","volume":"93","author":"Hu","year":"2021","journal-title":"J. Med. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.jaci.2020.07.009","article-title":"IL-6\u2013Based Mortality Risk Model for Hospitalized Patients with COVID-19","volume":"146","author":"Talayero","year":"2020","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1016\/S0140-6736(21)00676-0","article-title":"Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial","volume":"397","author":"Abani","year":"2021","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"REMAP-CAP Investigators, Gordon, A.C., Mouncey, P.R., Al-Beidh, F., Rowan, K.M., Nichol, A.D., Arabi, Y.M., Annane, D., Beane, A., and van Bentum-Puijk, W. (2021). Interleukin-6 Receptor Antagonists in Critically Ill Patients with COVID-19. N. Engl. J. Med., 384, 1491\u20131502.","DOI":"10.1056\/NEJMoa2100433"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1002\/art.22379","article-title":"Adalimumab for Long-Term Treatment of Psoriatic Arthritis: Forty-Eight Week Data from the Adalimumab Effectiveness in Psoriatic Arthritis Trial","volume":"56","author":"Gladman","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1136\/gut.2010.221127","article-title":"Adalimumab for Induction of Clinical Remission in Moderately to Severely Active Ulcerative Colitis: Results of a Randomised Controlled Trial","volume":"60","author":"Reinisch","year":"2011","journal-title":"Gut"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/j.dld.2018.10.024","article-title":"Real-World Efficacy of Adalimumab and Infliximab for Refractory Intestinal Behcet\u2019s Disease","volume":"51","author":"Sugimura","year":"2019","journal-title":"Dig. Liver Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1136\/ard.2003.013052","article-title":"Efficacy and Safety of Adalimumab as Monotherapy in Patients with Rheumatoid Arthritis for Whom Previous Disease Modifying Antirheumatic Drug Treatment Has Failed","volume":"63","author":"Atkins","year":"2004","journal-title":"Ann. Rheum. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2136","DOI":"10.1002\/art.21913","article-title":"Efficacy and Safety of Adalimumab in Patients with Ankylosing Spondylitis: Results of a Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial","volume":"54","author":"Kivitz","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1136\/annrheumdis-2020-217871","article-title":"COVID-19 Global Rheumatology Alliance. Characteristics Associated with Hospitalisation for COVID-19 in People with Rheumatic Disease: Data from the COVID-19 Global Rheumatology Alliance Physician-Reported Registry","volume":"79","author":"Gianfrancesco","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Rodrigues, T.S., De S\u00e1, K.S.G., Ishimoto, A.Y., Becerra, A., Oliveira, S., Almeida, L., Gon\u00e7alves, A.V., Perucello, D.B., Andrade, W.A., and Castro, R. (2021). Inflammasomes Are Activated in Response to SARS-CoV-2 Infection and Are Associated with COVID-19 Severity in Patients. J. Exp. Med., 218.","DOI":"10.1084\/jem.20201707"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.3899\/jrheum.200547","article-title":"Angiotensin-Converting Enzyme 2, a SARS-CoV-2 Receptor, Is Upregulated by Interleukin 6 through STAT3 Signaling in Synovial Tissues","volume":"47","author":"Mokuda","year":"2020","journal-title":"J. Rheumatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s41232-022-00252-4","article-title":"Expression of Factor XIII Originating from Synovial Fibroblasts and Macrophages Induced by Interleukin-6 Signaling","volume":"43","author":"Watanabe","year":"2023","journal-title":"Inflamm. Regen."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Tokunaga, T., Mokuda, S., Kohno, H., Yukawa, K., Kuranobu, T., Oi, K., Yoshida, Y., Hirata, S., and Sugiyama, E. (2020). TGF\u03b21 Regulates Human RANKL-Induced Osteoclastogenesis via Suppression of NFATc1 Expression. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030800"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Mokuda, S., Miyazaki, T., Ubara, Y., Kanno, M., Sugiyama, E., Takasugi, K., and Masumoto, J. (2015). CD1a+ Survivin+ Dendritic Cell Infiltration in Dermal Lesions of Systemic Sclerosis. Arthritis Res. Ther., 17.","DOI":"10.1186\/s13075-015-0785-0"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"177","DOI":"10.4265\/bio.26.177","article-title":"Ethanol Susceptibility of SARS-CoV-2 and Other Enveloped Viruses","volume":"26","author":"Nomura","year":"2021","journal-title":"Biocontrol Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1002\/jcb.10384","article-title":"Characterization of the neuropilin-1 Promoter; Gene Expression Is Mediated by the Transcription Factor Sp1","volume":"88","author":"Rossignol","year":"2003","journal-title":"J. Cell. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.cell.2020.05.042","article-title":"SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract","volume":"182","author":"Hou","year":"2020","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Lukassen, S., Chua, R.L., Trefzer, T., Kahn, N.C., Schneider, M.A., Muley, T., Winter, H., Meister, M., Veith, C., and Boots, A.W. (2020). SARS-CoV-2 Receptor ACE2 and TMPRSS2 Are Primarily Expressed in Bronchial Transient Secretory Cells. EMBO J., 39.","DOI":"10.15252\/embj.20105114"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1016\/j.csbj.2021.03.025","article-title":"Neuropilins: C-End Rule Peptides and Their Association with Nociception and COVID-19","volume":"19","author":"Jobe","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zhong, M., Lin, B., Pathak, J.L., Gao, H., Young, A.J., Wang, X., Liu, C., Wu, K., Liu, M., and Chen, J.M. (2020). ACE2 and Furin Expressions in Oral Epithelial Cells Possibly Facilitate COVID-19 Infection via Respiratory and Fecal-Oral Routes. Front. Med., 7.","DOI":"10.3389\/fmed.2020.580796"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/s41586-022-05542-y","article-title":"SARS-CoV-2 Infection and Persistence in the Human Body and Brain at Autopsy","volume":"612","author":"Stein","year":"2022","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1016\/j.immuni.2021.05.010","article-title":"Longitudinal Analysis Reveals That Delayed Bystander CD8+ T Cell Activation and Early Immune Pathology Distinguish Severe COVID-19 from Mild Disease","volume":"54","author":"Bergamaschi","year":"2021","journal-title":"Immunity"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7809","DOI":"10.1073\/pnas.0711241105","article-title":"Modulation of TNF-\u03b1-Converting Enzyme by the Spike Protein of SARS-CoV and ACE2 Induces TNF-\u03b1 Production and Facilitates Viral Entry","volume":"105","author":"Haga","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Zipeto, D., Palmeira, J.D.F., Arga\u00f1araz, G.A., and Arga\u00f1araz, E.R. (2020). ACE2\/ADAM17\/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.576745"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1097\/BRS.0b013e3181642a5e","article-title":"TNF-alpha Induces MMP2 Gelatinase Activity and MT1-MMP Expression in an In Vitro Model of Nucleus Pulposus Tissue Degeneration","volume":"33","author":"Pilliar","year":"2008","journal-title":"Spine"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/7\/1498\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:05:15Z","timestamp":1760126715000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/7\/1498"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,3]]},"references-count":37,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["v15071498"],"URL":"https:\/\/doi.org\/10.3390\/v15071498","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,3]]}}}