{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:36:15Z","timestamp":1790699775300,"version":"4.1.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T00:00:00Z","timestamp":1695254400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>\n                    Hearing loss is one of the 10 leading causes of disability worldwide. No drug therapies are currently available to protect or restore hearing. Inner ear auditory hair cells and the blood-labyrinth barrier (BLB) are critical for normal hearing, and the BLB between the systemic circulation and stria vascularis is crucial for maintaining cochlear and vestibular homeostasis. BLB defects are associated with inner ear diseases that lead to hearing loss, including vascular malformations, inflammation, and Meniere\u2019s disease (MD). Antibodies against proteins in the inner ear and cytokines in the cochlea, including IL-1\u03b1, TNF-\u03b1, and NF-k\u03b2, are detected in the blood of more than half of MD patients. There is also emerging evidence of inner ear inflammation in some diseases, including MD, progressive sensorineural hearing loss, otosclerosis, and sudden deafness. Here, we examined the effects of TNF-\u03b1, IL6, and LPS on human stria vascularis-derived primary endothelial cells cultured together with pericytes in a Transwell system. By measuring trans-endothelial electrical resistance, we found that TNF-\u03b1 causes the most significant disruption of the endothelial barrier. IL6 had a moderate influence on the barrier, whereas LPS had a minimal impact on barrier integrity. The prominent effect of TNF-\u03b1 on the barrier was confirmed in the expression of the major junctional genes responsible for forming the tight endothelial monolayer, the decreased expression of\n                    <jats:italic>ZO1<\/jats:italic>\n                    and\n                    <jats:italic>OCL<\/jats:italic>\n                    . We further tested permeability using 2\u2009\u03bcg of daptomycin (1,619\u2009Da), which does not pass the BLB under normal conditions, by measuring its passage through the barrier by HPLC. Treatment with TNF-\u03b1 resulted in higher permeability in treated samples compared to controls. LPS-treated cells behaved similarly to the untreated cells and did not show differences in permeability compared to control. The endothelial damage caused by TNF-\u03b1 was confirmed by decreased expression of an essential endothelial proteoglycan, syndecan1. These results allowed us to create an inflammatory environment model that increased BLB permeability in culture and mimicked an inflammatory state within the stria vascularis.\n                  <\/jats:p>","DOI":"10.3389\/fnmol.2023.1243370","type":"journal-article","created":{"date-parts":[[2023,9,23]],"date-time":"2023-09-23T08:25:41Z","timestamp":1695457541000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":38,"title":["Human blood-labyrinth barrier model to study the effects of cytokines and inflammation"],"prefix":"10.3389","volume":"16","author":[{"given":"Marijana","family":"Sekulic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raoul","family":"Puche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Bodmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vesna","family":"Petkovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,9,21]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"987","DOI":"10.3390\/genes11090987","article-title":"A systematic review of extreme phenotype strategies to search for rare variants in genetic studies of complex disorders","volume":"11","author":"Amanat","year":"2020","journal-title":"Genes"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1002\/path.2287","article-title":"TNF-mediated inflammatory disease","volume":"214","author":"Bradley","year":"2008","journal-title":"J. Pathol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"e112171","DOI":"10.1371\/journal.pone.0112171","article-title":"Intronic variants in the NFKB1 gene may influence hearing forecast in patients with unilateral sensorineural hearing loss in Meniere's disease","volume":"9","author":"Cabrera","year":"2014","journal-title":"PLoS One"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/B978-0-444-63437-5.00019-4","article-title":"Meni\u00e8re's disease","volume":"137","author":"Espinosa-Sanchez","year":"2016","journal-title":"Handb. Clin. Neurol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"109632","DOI":"10.1016\/j.clim.2023.109632","article-title":"Single-cell immune profiling of Meniere disease patients","volume":"252","author":"Flook","year":"2023","journal-title":"Clin. Immunol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1097\/MAO.0b013e31829e83df","article-title":"Endolymphatic hydrops in M\u00e9ni\u00e8re's disease: cause, consequence, or epiphenomenon?","volume":"34","author":"Foster","year":"2013","journal-title":"Otol. Neurotol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"5974","DOI":"10.1038\/s41598-018-23911-4","article-title":"Proinflammatory cytokines and response to molds in mononuclear cells of patients with Meniere disease","volume":"8","author":"Frejo","year":"2018","journal-title":"Sci. Rep."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"49","DOI":"10.21053\/ceo.2021.00920","article-title":"Cytokines and inflammation in Meniere disease","volume":"15","author":"Frejo","year":"2022","journal-title":"Clin. Exp. Otorhinol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1002\/jnr.20764","article-title":"Proinflammatory cytokines expression in noise-induced damaged cochlea","volume":"83","author":"Fujioka","year":"2006","journal-title":"J. Neurosci. Res."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1111\/coa.12432","article-title":"Current understanding of the pathogenesis of autoimmune inner ear disease: a review","volume":"40","author":"Goodall","year":"2015","journal-title":"Clin. Otolaryngol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1465","DOI":"10.1016\/S0002-9440(10)62363-2","article-title":"Matrix metalloproteinase dysregulation in the stria vascularis of mice with Alport syndrome: implications for capillary basement membrane pathology","volume":"166","author":"Gratton","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1177\/003591573803101112","article-title":"Observations on the pathology of M\u00e9ni\u00e8re's syndrome: (section of otology)","volume":"31","author":"Hallpike","year":"1938","journal-title":"Proc. R. Soc. Med."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"4603","DOI":"10.1039\/D2LC00657J","article-title":"Developing a transwell millifluidic device for studying blood\u2013brain barrier endothelium","volume":"22","author":"Harding","year":"2022","journal-title":"Lab Chip"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.heares.2019.02.015","article-title":"The aging cochlea: towards unraveling the functional contributions of strial dysfunction and synaptopathy","volume":"376","author":"Heeringa","year":"2019","journal-title":"Hear. Res."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"781031","DOI":"10.3389\/fneur.2022.781031","article-title":"Up-regulated expression of interferon-gamma, Interleukin-6 and tumor necrosis factor-alpha in the endolymphatic sac of Meniere's disease suggesting the local inflammatory response underlies the mechanism of this disease","volume":"13","author":"Huang","year":"2022","journal-title":"Front. Neurol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1038\/s41598-017-00330-5","article-title":"The blood labyrinthine barrier in the human normal and Meniere\u2019s disease macula utricle","volume":"7","author":"Ishiyama","year":"2017","journal-title":"Sci. Rep."},{"key":"ref17","first-page":"72","article-title":"Blood-labyrinth barrier and fluid dynamics of the inner ear","volume":"7","author":"Juhn","year":"2001","journal-title":"Int. Tinnitus J."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1016\/S0196-0709(82)80016-1","article-title":"Transport characteristics of the blood\u2013perilymph barrier","volume":"3","author":"Juhn","year":"1982","journal-title":"Am. J. Otolaryngol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1177\/000348948109000208","article-title":"Nature of blood-labyrinth barrier in experimental conditions","volume":"90","author":"Juhn","year":"1981","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"298ra118","DOI":"10.1126\/scitranslmed.aac5546","article-title":"Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity","volume":"7","author":"Koo","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1016\/s0194-5998(97)70026-3","article-title":"Breakdown of stria vascularis blood-labyrinth barrier in C3H\/lpr autoimmune disease mice","volume":"117","author":"Lin","year":"1997","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1097\/00129492-200501000-00013","article-title":"Pathophysiology of Meniere's syndrome: are symptoms caused by endolymphatic hydrops?","volume":"26","author":"Merchant","year":"2005","journal-title":"Otol. Neurotol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1177\/000348949510400611","article-title":"Hydrops-induced changes in cochlear blood flow","volume":"104","author":"Miller","year":"1995","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1038\/nprot.2013.033","article-title":"Isolation and culture of endothelial cells, pericytes and perivascular resident macrophage-like melanocytes from the young mouse ear","volume":"8","author":"Neng","year":"","journal-title":"Nat. Protoc."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1007\/s10162-012-0365-9","article-title":"Endothelial cell, pericyte, and perivascular resident macrophage-type melanocyte interactions regulate cochlear intrastrial fluid-blood barrier permeability","volume":"14","author":"Neng","year":"","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1903","DOI":"10.3174\/ajnr.A4822","article-title":"Blood-labyrinth barrier permeability in Meni\u00e8re disease and idiopathic sudden sensorineural hearing loss: findings on delayed Postcontrast 3D-FLAIR MRI","volume":"37","author":"Pakdaman","year":"2016","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"114816","DOI":"10.1016\/j.addr.2023.114816","article-title":"An overview of in vitro 3D models of the blood-brain barrier as a tool to predict the in vivo permeability of nanomedicines","volume":"196","author":"P\u00e9rez-l\u00f3pez","year":"2023","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1007\/s00251-013-0683-z","article-title":"Allelic variants in TLR10 gene may influence bilateral affectation and clinical course of Meniere's disease","volume":"65","author":"Requena","year":"2013","journal-title":"Immunogenetics"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/BF00214780","article-title":"Fine structure and permeability of capillaries in the stria vascularis and spiral ligament of the inner ear of the guinea pig","volume":"226","author":"Sakagami","year":"1982","journal-title":"Cell Tissue Res."},{"key":"ref30","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1288\/00005537-198708000-00020","article-title":"Mechanisms of endocochlear potential generation by stria vascularis","volume":"97","author":"Salt","year":"1987","journal-title":"Laryngoscope"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1007\/s10162-002-3025-7","article-title":"Proinflammatory cytokine expression in the endolymphatic sac during inner ear inflammation","volume":"4","author":"Satoh","year":"2003","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"862119","DOI":"10.3389\/fncel.2022.862119","article-title":"Lack of NHE6 and inhibition of NKCC1 associated with increased permeability in blood labyrinth barrier-derived endothelial cell layer","volume":"16","author":"Sekulic-Jablanovic","year":"2022","journal-title":"Front. Cell. Neurosci."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.clinimag.2014.09.014","article-title":"Delayed intravenous contrast-enhanced 3D FLAIR MRI in Meniere's disease: correlation of quantitative measures of endolymphatic hydrops with hearing","volume":"39","author":"Sepahdari","year":"2015","journal-title":"Clin. 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S. A."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"827","DOI":"10.4049\/jimmunol.2100745","article-title":"Bidirectional transport of IgE by CD23 in the inner ear of patients with Meniere\u2019s disease","volume":"208","author":"Zhang","year":"2022","journal-title":"J. Immunol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1007\/s10162-013-0403-2","article-title":"Characterization and inflammatory response of perivascular-resident macrophage-like melanocytes in the vestibular system","volume":"14","author":"Zhang","year":"2013","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1080\/16513860701305578","article-title":"In vivo MRI visualization of endolymphatic hydrops induced by keyhole limpet hemocyanin round window immunization","volume":"5","author":"Zou","year":"2007","journal-title":"Audiol. Med."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.joto.2016.11.002","article-title":"Inner ear barriers to nanomedicine-augmented drug delivery and imaging","volume":"11","author":"Zou","year":"2016","journal-title":"J. Otol."}],"container-title":["Frontiers in Molecular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2023.1243370\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,23]],"date-time":"2023-09-23T08:25:44Z","timestamp":1695457544000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2023.1243370\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,21]]},"references-count":42,"alternative-id":["10.3389\/fnmol.2023.1243370"],"URL":"https:\/\/doi.org\/10.3389\/fnmol.2023.1243370","relation":{},"ISSN":["1662-5099"],"issn-type":[{"value":"1662-5099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,21]]},"article-number":"1243370"}}