{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T20:27:27Z","timestamp":1775161647721,"version":"3.50.1"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2020,9,19]],"date-time":"2020-09-19T00:00:00Z","timestamp":1600473600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,9,19]],"date-time":"2020-09-19T00:00:00Z","timestamp":1600473600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100008898","name":"Retinologische Gesellschaft","doi-asserted-by":"crossref","award":["Dr. Gaide Award"],"award-info":[{"award-number":["Dr. Gaide Award"]}],"id":[{"id":"10.13039\/501100008898","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100008384","name":"Stifterverband","doi-asserted-by":"publisher","award":["Hermann-Wacker Foundation"],"award-info":[{"award-number":["Hermann-Wacker Foundation"]}],"id":[{"id":"10.13039\/501100008384","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Graefes Arch Clin Exp Ophthalmol"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>Systemic inflammation may be of importance in the development of AMD. RPE cells can recognize danger signals with toll-like receptors (TLR) and may react in a pro-inflammatory manner. In this study, we evaluated the basal and apical secretions of TNF\u03b1, IL-6, and IL-1\u03b2 in primary RPE cells and RPE\/choroid explant cells under basolateral stimulation of TLR2, 3, and 4; the effects on barrier function; and their influence on neuronal cell viability.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>RPE\/choroid tissue explants were prepared from porcine eyes and cultivated in modified Ussing chambers; primary porcine RPE cells on transwell plates. Cells were basally stimulated with agonists Pam2CSK4 (Pam; TLR2), polyinosinic\/polycytidylic acid (Poly I:C; TLR3), and lipopolysaccharide (LPS; TLR4) for 24 h. Supernatants were evaluated with ELISA for cytokines TNF\u03b1, IL-6, and IL-1\u03b2. Apical supernatants were applied to SHSY-5Y cells, and cell viability was evaluated in MTT assay. Barrier function was tested by measuring transepithelial electrical resistance (TER) and occludin immunostaining.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>None of the tested TLR agonists was toxic on RPE cells after 24 h of exposure. Unstimulated RPE cells secreted hardly any cytokines. Pam induced IL-6, IL-1\u00df, and TNF\u03b1 on the basal and apical sides at all concentrations tested. Poly I:C induced IL-6 and TNF\u03b1 primarily at the basal side at lower but on both sides at higher concentrations. LPS induced IL-6, IL-1\u00df, and TNF\u03b1 apically and basally at all concentrations tested. In the RPE\/choroid, a strong difference between apical and basal secretions could be found. IL-6 was constitutively secreted basally, but not apically, but was induced by all agonists on both sides. IL-1\u00df and TNF\u03b1 alpha were strongly induced on the basal side by all agonists. TER was reduced by all agonists, with Pam and LPS being effective in all concentrations tested. Occludin expression was unaltered, but the distribution was influenced by the agonists, with a less distinct localization at the cell borders after treatment. None of the agonists or supernatants of treated RPE and RPE\/choroid organ cultures exerted any effect on viability of SHSY-5Y cells.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Danger signals activating TLRs can induce polarized cytokine expression and contribute to the loss of barrier function in the RPE.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00417-020-04930-2","type":"journal-article","created":{"date-parts":[[2020,9,19]],"date-time":"2020-09-19T12:02:48Z","timestamp":1600516968000},"page":"413-424","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Basolateral activation with TLR agonists induces polarized cytokine release and reduces barrier function in RPE in vitro"],"prefix":"10.1007","volume":"259","author":[{"given":"Laura","family":"Terheyden","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johann","family":"Roider","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2709-1059","authenticated-orcid":false,"given":"Alexa","family":"Klettner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,9,19]]},"reference":[{"issue":"5","key":"4930_CR1","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1136\/bjophthalmol-2017-311258","volume":"102","author":"RRA Bourne","year":"2018","unstructured":"Bourne RRA, Jonas JB, Bron AM, Cicinelli MV, Das A, Flaxman SR, Friedman DS, Keeffe JE, Kempen JH, Leasher J, Limburg H, Naidoo K, Pesudovs K, Peto T, Saadine J, Silvester AJ, Tahhan N, Taylor HR, Varma R, Wong TY, Resnikoff S (2018) Prevalence and causes of vision loss in high-income countries and in Eastern and Central Europe in 2015: magnitude, temporal trends and projections. Br J Ophthalmol 102(5):575\u2013585. https:\/\/doi.org\/10.1136\/bjophthalmol-2017-311258","journal-title":"Br J Ophthalmol"},{"issue":"15","key":"4930_CR2","doi-asserted-by":"publisher","first-page":"6911","DOI":"10.1167\/iovs.16-21201","volume":"57","author":"JW Miller","year":"2016","unstructured":"Miller JW (2016) Beyond VEGF-the Weisenfeld lecture. Invest Ophthalmol Vis Sci 57(15):6911\u20136918. https:\/\/doi.org\/10.1167\/iovs.16-21201","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"3","key":"4930_CR3","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1152\/physrev.00021.2004","volume":"85","author":"O Strauss","year":"2005","unstructured":"Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85(3):845\u2013881. https:\/\/doi.org\/10.1152\/physrev.00021.2004","journal-title":"Physiol Rev"},{"key":"4930_CR4","first-page":"31","volume-title":"Recent Advances in Eye Research","author":"A Klettner","year":"2015","unstructured":"Klettner A (2015) The retinal pigment epithelium in the immune regulation of the retina. In: Hogarth A (ed) Recent Advances in Eye Research. Nova Science Publishers, New York, pp 31\u201352"},{"key":"4930_CR5","doi-asserted-by":"publisher","unstructured":"Naylor A, Hopkins A, Hudson N, Campbell M (2019) Tight junctions of the outer blood retina barrier. Int J Mol Sci 21(1). https:\/\/doi.org\/10.3390\/ijms21010211","DOI":"10.3390\/ijms21010211"},{"issue":"12","key":"4930_CR6","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1034\/j.1600-0854.2001.21202.x","volume":"2","author":"AD Marmorstein","year":"2001","unstructured":"Marmorstein AD (2001) The polarity of the retinal pigment epithelium. Traffic (Copenhagen, Denmark) 2(12):867\u2013872. https:\/\/doi.org\/10.1034\/j.1600-0854.2001.21202.x","journal-title":"Traffic (Copenhagen, Denmark)"},{"issue":"7","key":"4930_CR7","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1111\/jcmm.12070","volume":"17","author":"P Kay","year":"2013","unstructured":"Kay P, Yang YC, Paraoan L (2013) Directional protein secretion by the retinal pigment epithelium: roles in retinal health and the development of age-related macular degeneration. J Cell Mol Med 17(7):833\u2013843. https:\/\/doi.org\/10.1111\/jcmm.12070","journal-title":"J Cell Mol Med"},{"issue":"1","key":"4930_CR8","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.exer.2012.02.011","volume":"97","author":"F Treumer","year":"2012","unstructured":"Treumer F, Klettner A, Baltz J, Hussain AA, Miura Y, Brinkmann R, Roider J, Hillenkamp J (2012) Vectorial release of matrix metalloproteinases (MMPs) from porcine RPE-choroid explants following selective retina therapy (SRT): towards slowing the macular ageing process. Exp Eye Res 97(1):63\u201372. https:\/\/doi.org\/10.1016\/j.exer.2012.02.011","journal-title":"Exp Eye Res"},{"key":"4930_CR9","first-page":"736","volume":"21","author":"A Klettner","year":"2015","unstructured":"Klettner A, Kaya L, Flach J, Lassen J, Treumer F, Roider J (2015) Basal and apical regulation of VEGF-A and placenta growth factor in the RPE\/choroid and primary RPE. Mol Vis 21:736\u2013748","journal-title":"Mol Vis"},{"issue":"3","key":"4930_CR10","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1159\/000103235","volume":"39","author":"N Ebihara","year":"2007","unstructured":"Ebihara N, Chen L, Tokura T, Ushio H, Iwatsu M, Murakami A (2007) Distinct functions between toll-like receptors 3 and 9 in retinal pigment epithelial cells. Ophthalmic Res 39(3):155\u2013163. https:\/\/doi.org\/10.1159\/000103235","journal-title":"Ophthalmic Res"},{"issue":"1-2","key":"4930_CR11","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.jneuroim.2004.04.018","volume":"153","author":"MV Kumar","year":"2004","unstructured":"Kumar MV, Nagineni CN, Chin MS, Hooks JJ, Detrick B (2004) Innate immunity in the retina: toll-like receptor (TLR) signaling in human retinal pigment epithelial cells. J Neuroimmunol 153(1-2):7\u201315. https:\/\/doi.org\/10.1016\/j.jneuroim.2004.04.018","journal-title":"J Neuroimmunol"},{"issue":"3","key":"4930_CR12","doi-asserted-by":"publisher","first-page":"e211","DOI":"10.1111\/aos.12031","volume":"91","author":"A Klettner","year":"2013","unstructured":"Klettner A, Koinzer S, Meyer T, Roider J (2013) Toll-like receptor 3 activation in retinal pigment epithelium cells-mitogen-activated protein kinase pathways of cell death and vascular endothelial growth factor secretion. Acta Ophthalmol 91(3):e211\u2013e218. https:\/\/doi.org\/10.1111\/aos.12031","journal-title":"Acta Ophthalmol"},{"issue":"8","key":"4930_CR13","doi-asserted-by":"publisher","first-page":"e621","DOI":"10.1111\/aos.12472","volume":"92","author":"A Klettner","year":"2014","unstructured":"Klettner A, Hamann T, Schluter K, Lucius R, Roider J (2014) Retinal pigment epithelium cells alter the pro-inflammatory response of retinal microglia to TLR-3 stimulation. Acta Ophthalmol 92(8):e621\u2013e629. https:\/\/doi.org\/10.1111\/aos.12472","journal-title":"Acta Ophthalmol"},{"key":"4930_CR14","doi-asserted-by":"publisher","first-page":"19718","DOI":"10.1038\/srep19718","volume":"6","author":"L Ma","year":"2016","unstructured":"Ma L, Tang FY, Chu WK, Young AL, Brelen ME, Pang CP, Chen LJ (2016) Association of toll-like receptor 3 polymorphism rs3775291 with age-related macular degeneration: a systematic review and meta-analysis. Sci Rep 6:19718. https:\/\/doi.org\/10.1038\/srep19718","journal-title":"Sci Rep"},{"issue":"4","key":"4930_CR15","doi-asserted-by":"publisher","first-page":"1652","DOI":"10.1167\/iovs.07-1378","volume":"49","author":"AO Edwards","year":"2008","unstructured":"Edwards AO, Chen D, Fridley BL, James KM, Wu Y, Abecasis G, Swaroop A, Othman M, Branham K, Iyengar SK, Sivakumaran TA, Klein R, Klein BE, Tosakulwong N (2008) Toll-like receptor polymorphisms and age-related macular degeneration. Invest Ophthalmol Vis Sci 49(4):1652\u20131659. https:\/\/doi.org\/10.1167\/iovs.07-1378","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"14","key":"4930_CR16","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1056\/NEJMoa0802437","volume":"359","author":"Z Yang","year":"2008","unstructured":"Yang Z, Stratton C, Francis PJ, Kleinman ME, Tan PL, Gibbs D, Tong Z, Chen H, Constantine R, Yang X, Chen Y, Zeng J, Davey L, Ma X, Hau VS, Wang C, Harmon J, Buehler J, Pearson E, Patel S, Kaminoh Y, Watkins S, Luo L, Zabriskie NA, Bernstein PS, Cho W, Schwager A, Hinton DR, Klein ML, Hamon SC, Simmons E, Yu B, Campochiaro B, Sunness JS, Campochiaro P, Jorde L, Parmigiani G, Zack DJ, Katsanis N, Ambati J, Zhang K (2008) Toll-like receptor 3 and geographic atrophy in age-related macular degeneration. N Engl J Med 359(14):1456\u20131463. https:\/\/doi.org\/10.1056\/NEJMoa0802437","journal-title":"N Engl J Med"},{"issue":"11","key":"4930_CR17","doi-asserted-by":"publisher","first-page":"1449","DOI":"10.1093\/hmg\/ddi154","volume":"14","author":"S Zareparsi","year":"2005","unstructured":"Zareparsi S, Buraczynska M, Branham KE, Shah S, Eng D, Li M, Pawar H, Yashar BM, Moroi SE, Lichter PR, Petty HR, Richards JE, Abecasis GR, Elner VM, Swaroop A (2005) Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration. Hum Mol Genet 14(11):1449\u20131455. https:\/\/doi.org\/10.1093\/hmg\/ddi154","journal-title":"Hum Mol Genet"},{"issue":"6","key":"4930_CR18","doi-asserted-by":"publisher","first-page":"856","DOI":"10.3109\/02713683.2015.1067326","volume":"41","author":"M G\u00fcven","year":"2016","unstructured":"G\u00fcven M, Batar B, Mutlu T, Bostanc\u0131 M, Mete M, Aras C, \u00dcnal M (2016) Toll-like receptors 2 and 4 polymorphisms in age-related macular degeneration. Curr Eye Res 41(6):856\u2013861. https:\/\/doi.org\/10.3109\/02713683.2015.1067326","journal-title":"Curr Eye Res"},{"issue":"1","key":"4930_CR19","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/mt.2011.212","volume":"20","author":"ME Kleinman","year":"2012","unstructured":"Kleinman ME, Kaneko H, Cho WG, Dridi S, Fowler BJ, Blandford AD, Albuquerque RJ, Hirano Y, Terasaki H, Kondo M, Fujita T, Ambati BK, Tarallo V, Gelfand BD, Bogdanovich S, Baffi JZ, Ambati J (2012) Short-interfering RNAs induce retinal degeneration via TLR3 and IRF3. Molecular therapy : the journal of the American Society of Gene Therapy 20(1):101\u2013108. https:\/\/doi.org\/10.1038\/mt.2011.212","journal-title":"Molecular therapy : the journal of the American Society of Gene Therapy"},{"issue":"9","key":"4930_CR20","doi-asserted-by":"publisher","first-page":"4694","DOI":"10.1167\/iovs.09-4464","volume":"51","author":"T Fujimoto","year":"2010","unstructured":"Fujimoto T, Sonoda KH, Hijioka K, Sato K, Takeda A, Hasegawa E, Oshima Y, Ishibashi T (2010) Choroidal neovascularization enhanced by Chlamydia pneumoniae via Toll-like receptor 2 in the retinal pigment epithelium. Invest Ophthalmol Vis Sci 51(9):4694\u20134702. https:\/\/doi.org\/10.1167\/iovs.09-4464","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"21","key":"4930_CR21","doi-asserted-by":"publisher","first-page":"15326","DOI":"10.1074\/jbc.M112.448712","volume":"288","author":"H Kohno","year":"2013","unstructured":"Kohno H, Chen Y, Kevany BM, Pearlman E, Miyagi M, Maeda T, Palczewski K, Maeda A (2013) Photoreceptor proteins initiate microglial activation via Toll-like receptor 4 in retinal degeneration mediated by all-trans-retinal. J Biol Chem 288(21):15326\u201315341. https:\/\/doi.org\/10.1074\/jbc.M112.448712","journal-title":"J Biol Chem"},{"key":"4930_CR22","first-page":"1122","volume":"21","author":"Y Zhu","year":"2015","unstructured":"Zhu Y, Dai B, Li Y, Peng H (2015) C5a and toll-like receptor 4 crosstalk in retinal pigment epithelial cells. Mol Vis 21:1122\u20131129","journal-title":"Mol Vis"},{"issue":"3","key":"4930_CR23","doi-asserted-by":"publisher","first-page":"808","DOI":"10.3892\/ijmm.2015.2266","volume":"36","author":"SH Paeng","year":"2015","unstructured":"Paeng SH, Park WS, Jung WK, Lee DS, Kim GY, Choi YH, Seo SK, Jang WH, Choi JS, Lee YM, Park S, Choi IW (2015) YCG063 inhibits Pseudomonas aeruginosa LPS-induced inflammation in human retinal pigment epithelial cells through the TLR2-mediated AKT\/NF-kappaB pathway and ROS-independent pathways. Int J Mol Med 36(3):808\u2013816. https:\/\/doi.org\/10.3892\/ijmm.2015.2266","journal-title":"Int J Mol Med"},{"issue":"9","key":"4930_CR24","doi-asserted-by":"publisher","first-page":"6536","DOI":"10.1167\/iovs.10-6993","volume":"52","author":"M W\u00f6rnle","year":"2011","unstructured":"W\u00f6rnle M, Merkle M, Wolf A, Ribeiro A, Himmelein S, Kernt M, Kampik A, Eibl-Lindner KH (2011) Inhibition of TLR3-mediated proinflammatory effects by alkylphosphocholines in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 52(9):6536\u20136544. https:\/\/doi.org\/10.1167\/iovs.10-6993","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"2","key":"4930_CR25","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1111\/joim.12227","volume":"276","author":"CM Cheung","year":"2014","unstructured":"Cheung CM, Wong TY (2014) Is age-related macular degeneration a manifestation of systemic disease? New prospects for early intervention and treatment. J Intern Med 276(2):140\u2013153. https:\/\/doi.org\/10.1111\/joim.12227","journal-title":"J Intern Med"},{"key":"4930_CR26","doi-asserted-by":"publisher","first-page":"100825","DOI":"10.1016\/j.preteyeres.2019.100825","volume":"76","author":"MP Rozing","year":"2020","unstructured":"Rozing MP, Durhuus JA, Krogh Nielsen M, Subhi Y, Kirkwood TB, Westendorp RG, S\u00f8rensen TL (2020) Age-related macular degeneration: a two-level model hypothesis. Prog Retin Eye Res 76:100825. https:\/\/doi.org\/10.1016\/j.preteyeres.2019.100825","journal-title":"Prog Retin Eye Res"},{"issue":"6","key":"4930_CR27","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1016\/j.ajo.2013.08.003","volume":"156","author":"S Cao","year":"2013","unstructured":"Cao S, Ko A, Partanen M, Pakzad-Vaezi K, Merkur AB, Albiani DA, Kirker AW, Wang A, Cui JZ, Forooghian F, Matsubara JA (2013) Relationship between systemic cytokines and complement factor H Y402H polymorphism in patients with dry age-related macular degeneration. Am J Ophthalmol 156(6):1176\u20131183. https:\/\/doi.org\/10.1016\/j.ajo.2013.08.003","journal-title":"Am J Ophthalmol"},{"key":"4930_CR28","doi-asserted-by":"publisher","unstructured":"Nahavandipour A, Krogh Nielsen M, S\u00f8rensen TL, Subhi Y (2020) Systemic levels of interleukin-6 in patients with age-related macular degeneration: a systematic review and meta-analysis. Acta Ophthalmol. https:\/\/doi.org\/10.1111\/aos.14402","DOI":"10.1111\/aos.14402"},{"issue":"6","key":"4930_CR29","first-page":"B4872","volume":"61","author":"A Singh","year":"2014","unstructured":"Singh A (2014) Systemic changes in neovascular age-related macular degeneration. Danish Med J 61(6):B4872","journal-title":"Danish Med J"},{"issue":"10","key":"4930_CR30","doi-asserted-by":"publisher","first-page":"4523","DOI":"10.1167\/iovs.08-2055","volume":"49","author":"A Klettner","year":"2008","unstructured":"Klettner A, Roider J (2008) Comparison of bevacizumab, ranibizumab, and pegaptanib in vitro: efficiency and possible additional pathways. Invest Ophthalmol Vis Sci 49(10):4523\u20134527. https:\/\/doi.org\/10.1167\/iovs.08-2055","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"2","key":"4930_CR31","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1034\/j.1600-0420.2003.00030.x","volume":"81","author":"AK Wiencke","year":"2003","unstructured":"Wiencke AK, Kiilgaard JF, Nicolini J, Bundgaard M, Ropke C, La Cour M (2003) Growth of cultured porcine retinal pigment epithelial cells. Acta Ophthalmol Scand 81(2):170\u2013176. https:\/\/doi.org\/10.1034\/j.1600-0420.2003.00030.x","journal-title":"Acta Ophthalmol Scand"},{"key":"4930_CR32","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1007\/978-3-030-28384-1","volume-title":"Klettner A","author":"A Klettner","year":"2020","unstructured":"Klettner A (2020) Retinal pigment epithelium cell culture. In: Dithmar S (ed) Klettner A. Retinal Pigment Epithelium in Health and Disease, Springer Nature, pp 295\u2013306. https:\/\/doi.org\/10.1007\/978-3-030-28384-1"},{"key":"4930_CR33","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1007\/978-1-62703-640-5_2","volume":"1078","author":"J Kovalevich","year":"2013","unstructured":"Kovalevich J, Langford D (2013) Considerations for the use of SH-SY5Y neuroblastoma cells in neurobiology. Methods in molecular biology (Clifton, NJ) 1078:9\u201321. https:\/\/doi.org\/10.1007\/978-1-62703-640-5_2","journal-title":"Methods in molecular biology (Clifton, NJ)"},{"issue":"2","key":"4930_CR34","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1177\/2211068214561025","volume":"20","author":"B Srinivasan","year":"2015","unstructured":"Srinivasan B, Kolli AR, Esch MB, Abaci HE, Shuler ML, Hickman JJ (2015) TEER measurement techniques for in vitro barrier model systems. Journal of laboratory automation 20(2):107\u2013126. https:\/\/doi.org\/10.1177\/2211068214561025","journal-title":"Journal of laboratory automation"},{"key":"4930_CR35","volume-title":"Assay Guidance Manual","author":"TL Riss","year":"2004","unstructured":"Riss TL, Moravec RA, Niles AL, Duellman S, Benink HA, Worzella TJ, Minor L (2004) Cell viability assays. In: Sittampalam GS, Grossman A, Brimacombe K et al (eds) Assay Guidance Manual. Eli Lilly & Company and the National Center for Advancing Translational Sciences, Bethesda (MD)"},{"issue":"2","key":"4930_CR36","doi-asserted-by":"publisher","first-page":"e89150","DOI":"10.1371\/journal.pone.0089150","volume":"9","author":"M Dithmer","year":"2014","unstructured":"Dithmer M, Fuchs S, Shi Y, Schmidt H, Richert E, Roider J, Klettner A (2014) Fucoidan reduces secretion and expression of vascular endothelial growth factor in the retinal pigment epithelium and reduces angiogenesis in vitro. PloS one 9(2):e89150. https:\/\/doi.org\/10.1371\/journal.pone.0089150","journal-title":"PloS one"},{"key":"4930_CR37","doi-asserted-by":"publisher","unstructured":"Huang CY, Kuo CH, Chen PW (2017) Compressional-puffing pretreatment enhances neuroprotective effects of fucoidans from the brown seaweed Sargassum hemiphyllum on 6-hydroxydopamine-induced apoptosis in SH-SY5Y cells. Molecules (Basel, Switzerland) 23(1). https:\/\/doi.org\/10.3390\/molecules23010078","DOI":"10.3390\/molecules23010078"},{"key":"4930_CR38","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1007\/978-1-4939-8669-9_8","volume":"1834","author":"A Klettner","year":"2019","unstructured":"Klettner A, Miura Y (2019) Porcine RPE\/choroidal explant cultures. Methods Mol Biol (Clifton, NJ) 1834:109\u2013118. https:\/\/doi.org\/10.1007\/978-1-4939-8669-9_8","journal-title":"Methods Mol Biol (Clifton, NJ)"},{"key":"4930_CR39","first-page":"281","volume":"19","author":"A Klettner","year":"2013","unstructured":"Klettner A, Westhues D, Lassen J, Bartsch S, Roider J (2013) Regulation of constitutive vascular endothelial growth factor secretion in retinal pigment epithelium\/choroid organ cultures: p38, nuclear factor kappaB, and the vascular endothelial growth factor receptor-2\/phosphatidylinositol 3 kinase pathway. Mol Vis 19:281\u2013291","journal-title":"Mol Vis"},{"issue":"5","key":"4930_CR40","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1016\/j.preteyeres.2011.06.002","volume":"30","author":"LJ Rizzolo","year":"2011","unstructured":"Rizzolo LJ, Peng S, Luo Y, Xiao W (2011) Integration of tight junctions and claudins with the barrier functions of the retinal pigment epithelium. Prog Retin Eye Res 30(5):296\u2013323. https:\/\/doi.org\/10.1016\/j.preteyeres.2011.06.002","journal-title":"Prog Retin Eye Res"},{"issue":"3","key":"4930_CR41","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1159\/000252979","volume":"43","author":"Y Miura","year":"2010","unstructured":"Miura Y, Klettner A, Noelle B, Hasselbach H, Roider J (2010) Change of morphological and functional characteristics of retinal pigment epithelium cells during cultivation of retinal pigment epithelium-choroid perfusion tissue culture. Ophthalmic Res 43(3):122\u2013133. https:\/\/doi.org\/10.1159\/000252979","journal-title":"Ophthalmic Res"},{"key":"4930_CR42","first-page":"1915","volume":"15","author":"J Guduric-Fuchs","year":"2009","unstructured":"Guduric-Fuchs J, Ringland LJ, Gu P, Dellett M, Archer DB, Cogliati T (2009) Immunohistochemical study of pig retinal development. Mol Vis 15:1915\u20131928","journal-title":"Mol Vis"},{"issue":"4","key":"4930_CR43","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1006\/exer.2002.1181","volume":"74","author":"A Hendrickson","year":"2002","unstructured":"Hendrickson A, Hicks D (2002) Distribution and density of medium- and short-wavelength selective cones in the domestic pig retina. Exp Eye Res 74(4):435\u2013444. https:\/\/doi.org\/10.1006\/exer.2002.1181","journal-title":"Exp Eye Res"},{"issue":"3","key":"4930_CR44","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1016\/j.cvfa.2010.09.002","volume":"26","author":"S Middleton","year":"2010","unstructured":"Middleton S (2010) Porcine ophthalmology. The veterinary clinics of North America food animal practice 26(3):557\u2013572. https:\/\/doi.org\/10.1016\/j.cvfa.2010.09.002","journal-title":"The veterinary clinics of North America food animal practice"},{"issue":"11","key":"4930_CR45","doi-asserted-by":"publisher","first-page":"1747","DOI":"10.1007\/s00417-014-2742-z","volume":"252","author":"C Hettich","year":"2014","unstructured":"Hettich C, Wilker S, Mentlein R, Lucius R, Roider J, Klettner A (2014) The retinal pigment epithelium (RPE) induces FasL and reduces iNOS and Cox2 in primary monocytes. Graefe\u2019s archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 252(11):1747\u20131754. https:\/\/doi.org\/10.1007\/s00417-014-2742-z","journal-title":"Graefe\u2019s archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie"},{"issue":"13","key":"4930_CR46","first-page":"3513","volume":"33","author":"RH Quinn","year":"1992","unstructured":"Quinn RH, Miller SS (1992) Ion transport mechanisms in native human retinal pigment epithelium. Invest Ophthalmol Vis Sci 33(13):3513\u20133527","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"4930_CR47","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.exer.2013.12.018","volume":"126","author":"LJ Rizzolo","year":"2014","unstructured":"Rizzolo LJ (2014) Barrier properties of cultured retinal pigment epithelium. Exp Eye Res 126:16\u201326. https:\/\/doi.org\/10.1016\/j.exer.2013.12.018","journal-title":"Exp Eye Res"},{"key":"4930_CR48","first-page":"718","volume":"19","author":"S Cao","year":"2013","unstructured":"Cao S, Walker GB, Wang X, Cui JZ, Matsubara JA (2013) Altered cytokine profiles of human retinal pigment epithelium: oxidant injury and replicative senescence. Mol Vis 19:718\u2013728","journal-title":"Mol Vis"},{"issue":"11","key":"4930_CR49","doi-asserted-by":"publisher","first-page":"6404","DOI":"10.1167\/iovs.15-16898","volume":"56","author":"LK Mohr","year":"2015","unstructured":"Mohr LK, Hoffmann AV, Brandstetter C, Holz FG, Krohne TU (2015) Effects of inflammasome activation on secretion of inflammatory cytokines and vascular endothelial growth factor by retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 56(11):6404\u20136413. https:\/\/doi.org\/10.1167\/iovs.15-16898","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"1","key":"4930_CR50","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1046\/j.1365-2249.1998.00560.x","volume":"112","author":"GM Holtkamp","year":"1998","unstructured":"Holtkamp GM, Van Rossem M, de Vos AF, Willekens B, Peek R, Kijlstra A (1998) Polarized secretion of IL-6 and IL-8 by human retinal pigment epithelial cells. Clin Exp Immunol 112(1):34\u201343. https:\/\/doi.org\/10.1046\/j.1365-2249.1998.00560.x","journal-title":"Clin Exp Immunol"},{"issue":"1","key":"4930_CR51","first-page":"78","volume":"33","author":"SR Planck","year":"1992","unstructured":"Planck SR, Dang TT, Graves D, Tara D, Ansel JC, Rosenbaum JT (1992) Retinal pigment epithelial cells secrete interleukin-6 in response to interleukin-1. Invest Ophthalmol Vis Sci 33(1):78\u201382","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"1-3","key":"4930_CR52","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.toxlet.2003.12.022","volume":"149","author":"B Viviani","year":"2004","unstructured":"Viviani B, Bartesaghi S, Corsini E, Galli CL, Marinovich M (2004) Cytokines role in neurodegenerative events. Toxicol Lett 149(1-3):85\u201389. https:\/\/doi.org\/10.1016\/j.toxlet.2003.12.022","journal-title":"Toxicol Lett"},{"key":"4930_CR53","doi-asserted-by":"publisher","first-page":"e609","DOI":"10.1038\/cddis.2013.126","volume":"4","author":"M Leibinger","year":"2013","unstructured":"Leibinger M, Muller A, Gobrecht P, Diekmann H, Andreadaki A, Fischer D (2013) Interleukin-6 contributes to CNS axon regeneration upon inflammatory stimulation. Cell Death Dis 4:e609. https:\/\/doi.org\/10.1038\/cddis.2013.126","journal-title":"Cell Death Dis"},{"issue":"7","key":"4930_CR54","doi-asserted-by":"publisher","first-page":"2932","DOI":"10.1167\/iovs.05-1407","volume":"47","author":"RM Sappington","year":"2006","unstructured":"Sappington RM, Chan M, Calkins DJ (2006) Interleukin-6 protects retinal ganglion cells from pressure-induced death. Invest Ophthalmol Vis Sci 47(7):2932\u20132942. https:\/\/doi.org\/10.1167\/iovs.05-1407","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"3","key":"4930_CR55","doi-asserted-by":"publisher","first-page":"e1370","DOI":"10.1002\/term.2522","volume":"12","author":"JH Heo","year":"2018","unstructured":"Heo JH, Yoon JA, Ahn EK, Kim H, Urm SH, Oak CO, Yu BC, Lee SJ (2018) Intraperitoneal administration of adipose tissue-derived stem cells for the rescue of retinal degeneration in a mouse model via indigenous CNTF up-regulation by IL-6. J Tissue Eng Regen Med 12(3):e1370\u2013e1382. https:\/\/doi.org\/10.1002\/term.2522","journal-title":"J Tissue Eng Regen Med"},{"key":"4930_CR56","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.exer.2018.04.014","volume":"173","author":"AV Cioanca","year":"2018","unstructured":"Cioanca AV, McCluskey PJ, Eamegdool SS, Madigan MC (2018) Human choroidal melanocytes express functional Toll-like receptors (TLRs). Exp Eye Res 173:73\u201384. https:\/\/doi.org\/10.1016\/j.exer.2018.04.014","journal-title":"Exp Eye Res"},{"key":"4930_CR57","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.exer.2015.06.012","volume":"138","author":"EA Stewart","year":"2015","unstructured":"Stewart EA, Wei R, Branch MJ, Sidney LE, Amoaku WM (2015) Expression of Toll-like receptors in human retinal and choroidal vascular endothelial cells. Exp Eye Res 138:114\u2013123. https:\/\/doi.org\/10.1016\/j.exer.2015.06.012","journal-title":"Exp Eye Res"},{"key":"4930_CR58","first-page":"619","volume":"15","author":"W Chen","year":"2009","unstructured":"Chen W, Hu X, Zhao L, Li S, Lu H (2009) Expression of toll-like receptor 4 in uvea-resident tissue macrophages during endotoxin-induced uveitis. Mol Vis 15:619\u2013628","journal-title":"Mol Vis"},{"key":"4930_CR59","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/1742-2094-10-59","volume":"10","author":"C Song","year":"2013","unstructured":"Song C, Zhang Y, Dong Y (2013) Acute and subacute IL-1\u03b2 administrations differentially modulate neuroimmune and neurotrophic systems: possible implications for neuroprotection and neurodegeneration. J Neuroinflammation 10:59. https:\/\/doi.org\/10.1186\/1742-2094-10-59","journal-title":"J Neuroinflammation"},{"issue":"3-4","key":"4930_CR60","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1159\/000112104","volume":"16","author":"CC Chao","year":"1994","unstructured":"Chao CC, Hu S (1994) Tumor necrosis factor-alpha potentiates glutamate neurotoxicity in human fetal brain cell cultures. Dev Neurosci 16(3-4):172\u2013179. https:\/\/doi.org\/10.1159\/000112104","journal-title":"Dev Neurosci"},{"issue":"4","key":"4930_CR61","doi-asserted-by":"publisher","first-page":"2289","DOI":"10.3892\/mmr.2017.6252","volume":"15","author":"C Chen","year":"2017","unstructured":"Chen C, Guo D, Lu G (2017) Wogonin protects human retinal pigment epithelium cells from LPS-induced barrier dysfunction and inflammatory responses by regulating the TLR4\/NF-\u03baB signaling pathway. Mol Med Rep 15(4):2289\u20132295. https:\/\/doi.org\/10.3892\/mmr.2017.6252","journal-title":"Mol Med Rep"},{"issue":"8","key":"4930_CR62","doi-asserted-by":"publisher","first-page":"5016","DOI":"10.1167\/iovs.11-8311","volume":"53","author":"S Peng","year":"2012","unstructured":"Peng S, Gan G, Rao VS, Adelman RA, Rizzolo LJ (2012) Effects of proinflammatory cytokines on the claudin-19 rich tight junctions of human retinal pigment epithelium. Invest Ophthalmol Vis Sci 53(8):5016\u20135028. https:\/\/doi.org\/10.1167\/iovs.11-8311","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"1","key":"4930_CR63","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1186\/s12974-018-1106-8","volume":"15","author":"S Touhami","year":"2018","unstructured":"Touhami S, Beguier F, Augustin S, Charles-Messance H, Vignaud L, Nandrot EF, Reichman S, Forster V, Mathis T, Sahel JA, Bodaghi B, Guillonneau X, Sennlaub F (2018) Chronic exposure to tumor necrosis factor alpha induces retinal pigment epithelium cell dedifferentiation. J Neuroinflammation 15(1):85. https:\/\/doi.org\/10.1186\/s12974-018-1106-8","journal-title":"J Neuroinflammation"},{"key":"4930_CR64","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1007\/978-1-60761-938-3_5","volume":"686","author":"EA Runkle","year":"2011","unstructured":"Runkle EA, Antonetti DA (2011) The blood-retinal barrier: structure and functional significance. Methods Mol Biol (Clifton, NJ) 686:133\u2013148. https:\/\/doi.org\/10.1007\/978-1-60761-938-3_5","journal-title":"Methods Mol Biol (Clifton, NJ)"},{"issue":"1","key":"4930_CR65","doi-asserted-by":"publisher","first-page":"42","DOI":"10.3109\/08830185.2012.740535","volume":"32","author":"J Stein-Streilein","year":"2013","unstructured":"Stein-Streilein J (2013) Mechanisms of immune privilege in the posterior eye. Int Rev Immunol 32(1):42\u201356. https:\/\/doi.org\/10.3109\/08830185.2012.740535","journal-title":"Int Rev Immunol"},{"issue":"7","key":"4930_CR66","doi-asserted-by":"publisher","first-page":"2487","DOI":"10.1167\/iovs.04-1333","volume":"46","author":"H Xu","year":"2005","unstructured":"Xu H, Dawson R, Crane IJ, Liversidge J (2005) Leukocyte diapedesis in vivo induces transient loss of tight junction protein at the blood-retina barrier. Invest Ophthalmol Vis Sci 46(7):2487\u20132494. https:\/\/doi.org\/10.1167\/iovs.04-1333","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"Suppl 6","key":"4930_CR67","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.5301\/ejo.2010.6049","volume":"21","author":"J Cunha-Vaz","year":"2011","unstructured":"Cunha-Vaz J, Bernardes R, Lobo C (2011) Blood-retinal barrier. Eur J Ophthalmol 21(Suppl 6):S3\u2013S9. https:\/\/doi.org\/10.5301\/ejo.2010.6049","journal-title":"Eur J Ophthalmol"},{"issue":"1","key":"4930_CR68","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1167\/iovs.18-25721","volume":"60","author":"C Faber","year":"2019","unstructured":"Faber C, Juel HB, Jensen BAH, Christensen JP, Prause JU, Thomsen AR, Nissen MH (2019) Chemokine expression in murine RPE\/choroid in response to systemic viral infection and elevated levels of circulating interferon-\u03b3. Invest Ophthalmol Vis Sci 60(1):192\u2013201. https:\/\/doi.org\/10.1167\/iovs.18-25721","journal-title":"Invest Ophthalmol Vis Sci"}],"container-title":["Graefe's Archive for Clinical and Experimental Ophthalmology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00417-020-04930-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00417-020-04930-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00417-020-04930-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,19]],"date-time":"2021-09-19T00:48:51Z","timestamp":1632012531000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00417-020-04930-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,19]]},"references-count":68,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,2]]}},"alternative-id":["4930"],"URL":"https:\/\/doi.org\/10.1007\/s00417-020-04930-2","relation":{},"ISSN":["0721-832X","1435-702X"],"issn-type":[{"value":"0721-832X","type":"print"},{"value":"1435-702X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,19]]},"assertion":[{"value":"13 July 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 August 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 September 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 September 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The usage of the eyes for experimental purposes was conducted in agreement with the animal welfare officer of the University of Kiel. According to the German animal welfare act (TierSchG), it is not considered to be animal research, but an alternative to the use of animals in research.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Not applicable.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Code availability"}}]}}