{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T05:24:10Z","timestamp":1783056250943,"version":"3.54.6"},"reference-count":33,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2018,7,4]],"date-time":"2018-07-04T00:00:00Z","timestamp":1530662400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["310033-146833"],"award-info":[{"award-number":["310033-146833"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008273","name":"Novartis Foundation","doi-asserted-by":"publisher","award":["2017"],"award-info":[{"award-number":["2017"]}],"id":[{"id":"10.13039\/100008273","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ligue Pulmonaire Genevoise","award":["2017"],"award-info":[{"award-number":["2017"]}]},{"name":"CNRS and University of Orleans through International Associated Laboratory \u00abTB IMMUNITY\u00bb","award":["LIA Nb 236"],"award-info":[{"award-number":["LIA Nb 236"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pleural tuberculosis is one of the most frequent forms of extra-pulmonary tuberculosis observed in patients infected with Mycobacterium tuberculosis. Tumor Necrosis Factor (TNF) is a crucial cytokine needed to control tuberculosis infection that remains a leading cause of morbidity and mortality worldwide. TNF blockade compromises host immunity and may increase the risk of reactivation of latent infection resulting in overt pulmonary, pleural and extra-pulmonary tuberculosis. While TNF signaling is mainly considered pro-inflammatory, its requirement for the anti-inflammation process involved in the resolution of infection and tissue repair is less explored. Our study analyzes the role of TNF and TNF receptors in the control of the inflammatory process associated with Bacillus Calmette-Gu\u00e9rin (BCG)-induced pleurisy. This study shows that the absence of TNF causes exacerbated inflammation in the pleural cavity of BCG-infected mice which is controlled by the transmembrane TNF (tmTNF) expression. The lack of TNF is associated with an impaired cellular expression and shedding of TNFR2 in the pleural cavity. The presence of tmTNF restores the normal expression of TNFR2 on myeloid cells during BCG-induced pleurisy. We also show that absence of TNFR1 affects the expression of TNFR2 on pleural cells and inflammation in the pleural cavity of BCG-infected mice. In conclusion, tmTNF but not soluble TNF prevents pleural cavity inflammation leading to attenuation and the resolution of the inflammatory process caused by mycobacterial pleurisy in association with the expression of TNFR2 on myeloid cells.<\/jats:p>","DOI":"10.3390\/ijms19071959","type":"journal-article","created":{"date-parts":[[2018,7,4]],"date-time":"2018-07-04T12:23:02Z","timestamp":1530706982000},"page":"1959","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Transmembrane TNF and Partially TNFR1 Regulate TNFR2 Expression and Control Inflammation in Mycobacterial-Induced Pleurisy"],"prefix":"10.3390","volume":"19","author":[{"given":"Husnu","family":"Uysal","sequence":"first","affiliation":[{"name":"Department of Pathology and Immunology, Centre Medical Universitaire (CMU), Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2334-0361","authenticated-orcid":false,"given":"Leslie","family":"Chavez-Galan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Centre Medical Universitaire (CMU), Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Vesin","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Centre Medical Universitaire (CMU), Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Blaser","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Centre Medical Universitaire (CMU), Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahdia","family":"Benkhoucha","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Centre Medical Universitaire (CMU), Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2897-8230","authenticated-orcid":false,"given":"Bernhard","family":"Ryffel","sequence":"additional","affiliation":[{"name":"Centre National de la Recherche Scientifique, UMR7355, and Experimental and Molecular Immunology and Neurogenetics, University of Orl\u00e9ans, 45100 Orl\u00e9ans, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie F. J.","family":"Quesniaux","sequence":"additional","affiliation":[{"name":"Centre National de la Recherche Scientifique, UMR7355, and Experimental and Molecular Immunology and Neurogenetics, University of Orl\u00e9ans, 45100 Orl\u00e9ans, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Garcia","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Centre Medical Universitaire (CMU), Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/978-1-4419-6612-4_20","article-title":"Roles of soluble and membrane TNF and related ligands in mycobacterial infections: Effects of selective and non-selective TNF inhibitors during infection","volume":"691","author":"Garcia","year":"2011","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.cytogfr.2014.02.001","article-title":"Lymphotoxin and TNF: How it all began-a tribute to the travelers","volume":"25","author":"Ruddle","year":"2014","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S1359-6101(96)00026-3","article-title":"The potential biological and clinical significance of the soluble tumor necrosis factor receptors","volume":"7","author":"Aderka","year":"1996","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_4","first-page":"157","article-title":"Variation in serum levels of the soluble TNF receptors among healthy individuals","volume":"11","author":"Aderka","year":"1992","journal-title":"Lymphokine Cytokine Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.1038\/502S13a","article-title":"Perspective: Weigh all TB risks","volume":"502","author":"Dye","year":"2013","journal-title":"Nature"},{"key":"ref_6","unstructured":"Olleros, M.L., and Garcia, I. (2009). The roles of tumor necrosis factor and other macrophage-derived cytokines in host defense mechanisms during the course of mycobacterium tuberculosis infection. Current Topics on the Profiles of Host Immunological Response to Mycobacterial Infections, Singpost Special Immunol book Ed."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.cell.2013.03.022","article-title":"TNF dually mediates resistance and susceptibility to mycobacteria via mitochondrial reactive oxygen species","volume":"153","author":"Roca","year":"2013","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/1074-7613(95)90001-2","article-title":"Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice","volume":"2","author":"Flynn","year":"1995","journal-title":"Immunity"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4094","DOI":"10.1172\/JCI64115","article-title":"TNF signaling drives myeloid-derived suppressor cell accumulation","volume":"122","author":"Zhao","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1172\/JCI45005","article-title":"Soluble TNFRp75 regulates host protective immunity against Mycobacterium tuberculosis","volume":"124","author":"Keeton","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"22454","DOI":"10.1038\/srep22454","article-title":"Innate myeloid cell TNFR1 mediates first line defence against primary Mycobacterium tuberculosis infection","volume":"6","author":"Segueni","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1056\/NEJMoa011110","article-title":"Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent","volume":"345","author":"Keane","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_13","first-page":"61","article-title":"Extrapulmonary tuberculosis: Are statistical reports accurate?","volume":"2","author":"Kulchavenya","year":"2014","journal-title":"Ther. Adv. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1183\/09031936.03.00403902","article-title":"Immunological mechanisms in pleural disease","volume":"21","author":"Antony","year":"2003","journal-title":"Eur. Respir. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1093\/ije\/dyh392","article-title":"BCG vaccination scar associated with better childhood survival in Guinea-Bissau","volume":"34","author":"Roth","year":"2005","journal-title":"Int. J. Epidemiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1016\/S0140-6736(98)07422-4","article-title":"BCG immunotherapy of bladder cancer: 20 years on","volume":"353","author":"Alexandroff","year":"1999","journal-title":"Lancet"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.1016\/j.ajpath.2016.05.015","article-title":"Tumor Necrosis Factor and Its Receptors Are Crucial to Control Mycobacterium Bovis Bacillus Calmette-Guerin Pleural Infection in a Murine Model","volume":"186","author":"Vesin","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"999","DOI":"10.3389\/fimmu.2017.00999","article-title":"Transmembrane Tumor Necrosis Factor Controls Myeloid-Derived Suppressor Cell Activity via TNF Receptor 2 and Protects from Excessive Inflammation during BCG-Induced Pleurisy","volume":"8","author":"Vesin","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Olleros, M.L., Vesin, D., Bisig, R., Santiago-Raber, M.L., Schuepbach-Mallepell, S., Kollias, G., Gaide, O., and Garcia, I. (2012). Membrane-bound TNF induces protective immune responses to M. bovis BCG infection: Regulation of memTNF and TNF receptors comparing two memTNF molecules. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0031469"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1002\/art.1780351008","article-title":"Increased levels of soluble tumor necrosis factor receptors in the sera and synovial fluid of patients with rheumatic diseases","volume":"35","author":"Cope","year":"1992","journal-title":"Arthritis Rheum."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1038\/labinvest.3780146","article-title":"Lethal Mycobacterium bovis Bacillus Calmette Guerin infection in nitric oxide synthase 2-deficient mice: Cell-mediated immunity requires nitric oxide synthase 2","volume":"80","author":"Garcia","year":"2000","journal-title":"Lab. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3612","DOI":"10.1128\/IAI.00743-15","article-title":"Nedospasov, and I. Garcia, Control of Mycobacterial Infections in Mice Expressing Human Tumor Necrosis Factor (TNF) but Not Mouse TNF","volume":"83","author":"Olleros","year":"2015","journal-title":"Infect. Immun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/S0021-9258(19)40049-5","article-title":"Two tumor necrosis factor-binding proteins purified from human urine. Evidence for immunological cross-reactivity with cell surface tumor necrosis factor receptors","volume":"265","author":"Engelmann","year":"1990","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2636","DOI":"10.4049\/jimmunol.161.5.2636","article-title":"Pathogenic Mycobacterium tuberculosis evades apoptosis of host macrophages by release of TNF-R2, resulting in inactivation of TNF-alpha","volume":"161","author":"Keane","year":"1998","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3550","DOI":"10.4049\/jimmunol.152.7.3550","article-title":"TNF induces internalization of the p60 receptor and shedding of the p80 receptor","volume":"152","author":"Higuchi","year":"1994","journal-title":"J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/iid3.19","article-title":"Myeloid suppressor cells require membrane TNFR2 expression for suppressive activity","volume":"2","author":"Polz","year":"2014","journal-title":"Immun. Inflamm. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1002\/eji.201041205","article-title":"TNF optimally activatives regulatory T cells by inducing TNF receptor superfamily members TNFR2, 4\u20131BB and OX40","volume":"41","author":"Hamano","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1172\/JCI18991","article-title":"TNF-alpha is a critical negative regulator of type 1 immune activation during intracellular bacterial infection","volume":"113","author":"Zganiacz","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1086\/597204","article-title":"Dominant-negative tumor necrosis factor protects from Mycobacterium bovis Bacillus Calmette Guerin (BCG) and endotoxin-induced liver injury without compromising host immunity to BCG and Mycobacterium tuberculosis","volume":"199","author":"Olleros","year":"2009","journal-title":"J. Infect. Dis."},{"key":"ref_30","first-page":"124","article-title":"Tumor necrosis factor neutralization combined with chemotherapy enhances Mycobacterium tuberculosis clearance and reduces lungpathology","volume":"2","author":"Bourigault","year":"2013","journal-title":"Am. J. Clin. Exp. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Skerry, C., Harper, J., Klunk, M., Bishai, W.R., and Jain, S.K. (2012). Adjunctive TNF inhibition with standard treatment enhances bacterial clearance in a murine model of necrotic TB granulomas. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0039680"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8093","DOI":"10.1073\/pnas.94.15.8093","article-title":"Characterization of tumor necrosis factor-deficient mice","volume":"94","author":"Marino","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S1074-7613(01)00215-1","article-title":"Membrane-bound TNF supports secondary lymphoid organ structure but is subservient to secreted TNF in driving autoimmune inflammation","volume":"15","author":"Ruuls","year":"2001","journal-title":"Immunity"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/7\/1959\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:11:17Z","timestamp":1760195477000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/7\/1959"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,7,4]]},"references-count":33,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2018,7]]}},"alternative-id":["ijms19071959"],"URL":"https:\/\/doi.org\/10.3390\/ijms19071959","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,7,4]]}}}