{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:37:38Z","timestamp":1790807858660,"version":"4.1.0"},"reference-count":69,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T00:00:00Z","timestamp":1628812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"fort\u00fcne-Programm, T\u00fcbingen","award":["2640-0-0"],"award-info":[{"award-number":["2640-0-0"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is a degenerative disease of the macula, where retinal pigment epithelium (RPE) cells are damaged in the early stages of the disease, and chronic inflammatory processes may be involved. Besides aging and lifestyle factors as drivers of AMD, a strong genetic association to AMD is found in genes of the complement system, with a single polymorphism in the complement factor H gene (CFH), accounting for the majority of AMD risk. However, the exact mechanism of CFH dysregulation confers such a great risk for AMD and its role in RPE cell homeostasis is unclear. To explore the role of endogenous CFH locally in RPE cells, we silenced CFH in human hTERT-RPE1 cells. We demonstrate that endogenously expressed CFH in RPE cells modulates inflammatory cytokine production and complement regulation, independent of external complement sources, or stressors. We show that loss of the factor H protein (FH) results in increased levels of inflammatory mediators (e.g., IL-6, IL-8, GM-CSF) and altered levels of complement proteins (e.g., C3, CFB upregulation, and C5 downregulation) that are known to play a role in AMD. Moreover, our results identify the NF-\u03baB pathway as the major pathway involved in regulating these inflammatory and complement factors. Our findings suggest that in RPE cells, FH and the NF-\u03baB pathway work in synergy to maintain inflammatory and complement balance, and in case either one of them is dysregulated, the RPE microenvironment changes towards a proinflammatory AMD-like phenotype.<\/jats:p>","DOI":"10.3390\/ijms22168727","type":"journal-article","created":{"date-parts":[[2021,8,15]],"date-time":"2021-08-15T21:43:55Z","timestamp":1629063835000},"page":"8727","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["CFH Loss in Human RPE Cells Leads to Inflammation and Complement System Dysregulation via the NF-\u03baB Pathway"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6357-1500","authenticated-orcid":false,"given":"Angela","family":"Armento","sequence":"first","affiliation":[{"name":"Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5066-5540","authenticated-orcid":false,"given":"Tiziana L.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inga","family":"Sonntag","sequence":"additional","affiliation":[{"name":"Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4485-5580","authenticated-orcid":false,"given":"David A.","family":"Merle","sequence":"additional","affiliation":[{"name":"Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"},{"name":"Department of Ophthalmology, Medical University of Graz, 8036 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Ali","family":"Jarboui","sequence":"additional","affiliation":[{"name":"Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Kilger","sequence":"additional","affiliation":[{"name":"Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8394-8355","authenticated-orcid":false,"given":"Simon J.","family":"Clark","sequence":"additional","affiliation":[{"name":"Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"},{"name":"Department for Ophthalmology, University Eye Clinic, Eberhard Karls University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"},{"name":"Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2209-2113","authenticated-orcid":false,"given":"Marius","family":"Ueffing","sequence":"additional","affiliation":[{"name":"Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"},{"name":"Department for Ophthalmology, University Eye Clinic, Eberhard Karls University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.3410\/B2-3","article-title":"Ocular immune privilege","volume":"2","author":"Zhou","year":"2010","journal-title":"F1000 Biol. Rep."},{"key":"ref_2","unstructured":"Ryan, S.J., Sadda, S.R., Hinton, D.R., Schachat, A.P., Sadda, S.R., Wilkinson, C.P., Wiedemann, P., and Schachat, A.P. (2013). Chapter 20\u2014Structure, Function, and Pathology of Bruch\u2019s Membrane. Retina, W.B. Saunders. [5th ed.]."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.3389\/fimmu.2017.01778","article-title":"Bruch\u2019s Membrane Compartmentalizes Complement Regulation in the Eye with Implications for Therapeutic Design in Age-Related Macular Degeneration","volume":"8","author":"Clark","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1152\/physrev.00021.2004","article-title":"The retinal pigment epithelium in visual function","volume":"85","author":"Strauss","year":"2005","journal-title":"Physiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.3389\/fimmu.2019.01975","article-title":"Microglia in Retinal Degeneration","volume":"10","author":"Rashid","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/path.4266","article-title":"Mechanisms of age-related macular degeneration and therapeutic opportunities","volume":"232","author":"LeCouter","year":"2014","journal-title":"J. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3347","DOI":"10.1038\/s41467-019-11262-1","article-title":"A systems biology approach towards understanding and treating non-neovascular age-related macular degeneration","volume":"10","author":"Handa","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/j.ajo.2003.11.069","article-title":"The epidemiology of age-related macular degeneration","volume":"137","author":"Klein","year":"2004","journal-title":"Am. J. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1096\/fasebj.14.7.835","article-title":"Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease","volume":"14","author":"Mullins","year":"2000","journal-title":"FASEB J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2526","DOI":"10.1016\/j.ophtha.2012.06.042","article-title":"Genetic studies of age-related macular degeneration: Lessons, challenges, and opportunities for disease management","volume":"119","author":"Priya","year":"2012","journal-title":"Ophthalmology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.ophtha.2020.08.031","article-title":"Predicting Progression to Advanced Age-Related Macular Degeneration from Clinical, Genetic, and Lifestyle Factors Using Machine Learning","volume":"128","author":"Ajana","year":"2020","journal-title":"Ophthalmology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1111\/opo.12675","article-title":"Risk factors for progression of age-related macular degeneration","volume":"40","author":"Heesterbeek","year":"2020","journal-title":"Ophthalmic Physiol. Opt."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1146\/annurev-genom-090413-025610","article-title":"Age-related macular degeneration: Genetics and biology coming together","volume":"15","author":"Fritsche","year":"2014","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/ni.1923","article-title":"Complement: A key system for immune surveillance and homeostasis","volume":"11","author":"Ricklin","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1189\/jlb.1102574","article-title":"Ocular immune privilege: The eye takes a dim but practical view of immunity and inflammation","volume":"74","author":"Streilein","year":"2003","journal-title":"J. Leukoc. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2753","DOI":"10.1016\/j.molimm.2009.04.027","article-title":"The role of the anaphylatoxins in health and disease","volume":"46","author":"Klos","year":"2009","journal-title":"Mol. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1007\/s00018-019-03419-4","article-title":"The role of lymphocytes and phagocytes in age-related macular degeneration (AMD)","volume":"77","author":"Behnke","year":"2020","journal-title":"Cell Mol. Life Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2989","DOI":"10.7150\/ijbs.49890","article-title":"The Role of Inflammation in Age-Related Macular Degeneration","volume":"16","author":"Tan","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1167\/iovs.61.3.18","article-title":"Complement Activation Levels Are Related to Disease Stage in AMD","volume":"61","author":"Heesterbeek","year":"2020","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4870","DOI":"10.1167\/iovs.15-17009","article-title":"Assessment of Proteins Associated With Complement Activation and Inflammation in Maculae of Human Donors Homozygous Risk at Chromosome 1 CFH-to-F13B","volume":"56","author":"Keenan","year":"2015","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1126\/science.1110189","article-title":"Complement factor H polymorphism and age-related macular degeneration","volume":"308","author":"Edwards","year":"2005","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/BF00346588","article-title":"Sequence polymorphism of human complement factor H","volume":"27","author":"Day","year":"1988","journal-title":"Immunogenetics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4962","DOI":"10.4049\/jimmunol.1401613","article-title":"Identification of factor H-like protein 1 as the predominant complement regulator in Bruch\u2019s membrane: Implications for age-related macular degeneration","volume":"193","author":"Clark","year":"2014","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Armento, A., Ueffing, M., and Clark, S.J. (2021). The complement system in age-related macular degeneration. Cell. Mol. Life Sci.","DOI":"10.1007\/s00018-021-03796-9"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3398","DOI":"10.1016\/j.molimm.2007.02.012","article-title":"Defective complement control of factor H (Y402H) and FHL-1 in age-related macular degeneration","volume":"44","author":"Skerka","year":"2007","journal-title":"Mol. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"30192","DOI":"10.1074\/jbc.M110.103986","article-title":"Impaired binding of the age-related macular degeneration-associated complement factor H 402H allotype to Bruch\u2019s membrane in human retina","volume":"285","author":"Clark","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"13757","DOI":"10.1073\/pnas.1121309109","article-title":"Complement factor H genotypes impact risk of age-related macular degeneration by interaction with oxidized phospholipids","volume":"109","author":"Shaw","year":"2012","journal-title":"Proc. Natl. Acad. Sci.USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"22889","DOI":"10.1038\/srep22889","article-title":"Complement factor H binding of monomeric C-reactive protein downregulates proinflammatory activity and is impaired with at risk polymorphic CFH variants","volume":"6","author":"Molins","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1038\/s41598-017-18395-7","article-title":"C-reactive protein and pentraxin-3 binding of factor H-like protein 1 differs from complement factor H: Implications for retinal inflammation","volume":"8","author":"Swinkels","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Mannes, M., Dopler, A., Huber-Lang, M., and Schmidt, C.Q. (2020). Tuning the Functionality by Splicing: Factor H and Its Alternative Splice Variant FHL-1 Share a Gene but Not All Functions. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.596415"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10320","DOI":"10.1038\/s41598-020-67292-z","article-title":"Loss of Complement Factor H impairs antioxidant capacity and energy metabolism of human RPE cells","volume":"10","author":"Armento","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"a000034","DOI":"10.1101\/cshperspect.a000034","article-title":"The NF-kappaB family of transcription factors and its regulation","volume":"1","author":"Oeckinghaus","year":"2009","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"918","DOI":"10.2174\/1570159X18666200207120949","article-title":"Role of Nuclear Factor Kappa B (NF-kappaB) Signalling in Neurodegenerative Diseases: An Mechanistic Approach","volume":"18","author":"Singh","year":"2020","journal-title":"Curr. Neuropharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"109687","DOI":"10.1016\/j.cellsig.2020.109687","article-title":"Role of HMGB1 signaling in the inflammatory process in diabetic retinopathy","volume":"73","author":"Steinle","year":"2020","journal-title":"Cell Signal."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Macchioni, L., Chiasserini, D., Mezzasoma, L., Davidescu, M., Orvietani, P.L., Fettucciari, K., Salviati, L., Cellini, B., and Bellezza, I. (2020). Crosstalk between Long-Term Sublethal Oxidative Stress and Detrimental Inflammation as Potential Drivers for Age-Related Retinal Degeneration. Antioxidants, 10.","DOI":"10.3390\/antiox10010025"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"108391","DOI":"10.1016\/j.exer.2020.108391","article-title":"Evolution of oxidative stress, inflammation and neovascularization in the choroid and retina in a subretinal lipid induced age-related macular degeneration model","volume":"203","author":"Kim","year":"2021","journal-title":"Exp. Eye Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/wsbm.1331","article-title":"Signaling via the NF\u03baB system","volume":"8","author":"Mitchell","year":"2016","journal-title":"Wiley Interdiscip. Rev. Syst. Biol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"16651","DOI":"10.1073\/pnas.0705079104","article-title":"Complement factor H deficiency in aged mice causes retinal abnormalities and visual dysfunction","volume":"104","author":"Coffey","year":"2007","journal-title":"Proc. Natl. Acad. Sci.USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.ajpath.2014.08.026","article-title":"Expression of human complement factor H prevents age-related macular degeneration-like retina damage and kidney abnormalities in aged Cfh knockout mice","volume":"185","author":"Ding","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref_40","first-page":"4039","article-title":"Complement factor H-deficient mice develop spontaneous hepatic tumors","volume":"130","author":"Laskowski","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1021\/acsptsci.0c00176","article-title":"Investigation of the Structure-Activity Relationships of Psilocybin Analogues","volume":"4","author":"Klein","year":"2021","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.1002\/stem.2708","article-title":"An Induced Pluripotent Stem Cell Patient Specific Model of Complement Factor H (Y402H) Polymorphism Displays Characteristic Features of Age-Related Macular Degeneration and Indicates a Beneficial Role for UV Light Exposure","volume":"35","author":"Hallam","year":"2017","journal-title":"Stem. Cells"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Ebeling, M.C., Geng, Z., Kapphahn, R.J., Roehrich, H., Montezuma, S.R., Dutton, J.R., and Ferrington, D.A. (2021). Impaired Mitochondrial Function in iPSC-Retinal Pigment Epithelium with the Complement Factor H Polymorphism for Age-Related Macular Degeneration. Cells, 10.","DOI":"10.3390\/cells10040789"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1002\/sctm.20-0211","article-title":"Complement modulation reverses pathology in Y402H-retinal pigment epithelium cell model of age-related macular degeneration by restoring lysosomal function","volume":"9","author":"Cerniauskas","year":"2020","journal-title":"Stem. Cells Transl. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.redox.2015.11.011","article-title":"Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration","volume":"7","author":"Marazita","year":"2016","journal-title":"Redox Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1111\/aos.14402","article-title":"Systemic levels of interleukin-6 in patients with age-related macular degeneration: A systematic review and meta-analysis","volume":"98","author":"Nahavandipour","year":"2020","journal-title":"Acta Ophthalmol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1167\/tvst.10.1.14","article-title":"Common Genes Involved in Autophagy, Cellular Senescence and the Inflammatory Response in AMD and Drug Discovery Identified via Biomedical Databases","volume":"10","author":"Wang","year":"2021","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1046\/j.1365-2249.1999.00805.x","article-title":"Cytokine regulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) production by human retinal pigment epithelial cells","volume":"115","author":"Crane","year":"1999","journal-title":"Clin. Exp. Immunol."},{"key":"ref_49","first-page":"264","article-title":"CFH Y402H polymorphism is associated with elevated vitreal GM-CSF and choroidal macrophages in the postmortem human eye","volume":"21","author":"Wang","year":"2015","journal-title":"Mol. Vis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1161\/ATVBAHA.117.309451","article-title":"Plasminogen Activator Inhibitor-1 Is a Marker and a Mediator of Senescence","volume":"37","author":"Vaughan","year":"2017","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1096\/fsb2fj000393com","article-title":"Influence of plasminogen activator inhibitor type 1 on choroidal neovascularization","volume":"15","author":"Lambert","year":"2001","journal-title":"FASEB J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1038\/383441a0","article-title":"The serpin PAI-1 inhibits cell migration by blocking integrin \u03b1v\u03b23 binding to vitronectin","volume":"383","author":"Stefansson","year":"1996","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"14175","DOI":"10.1038\/s41598-021-93708-5","article-title":"FHL-1 interacts with human RPE cells through the \u03b15\u03b21 integrin and confers protection against oxidative stress","volume":"11","author":"Choudhury","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"33123","DOI":"10.1038\/srep33123","article-title":"Chemokine CXCL1 mediated neutrophil recruitment: Role of glycosaminoglycan interactions","volume":"6","author":"Sawant","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1167\/iovs.18-24387","article-title":"Cytokine Profiling in Patients With Exudative Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy","volume":"60","author":"Agrawal","year":"2019","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s12974-014-0224-1","article-title":"Chemokine-mediated inflammation in the degenerating retina is coordinated by M\u00fcller cells, activated microglia, and retinal pigment epithelium","volume":"12","author":"Rutar","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3240","DOI":"10.1167\/iovs.12-11483","article-title":"Mature dendritic cell suppression by IL-1 receptor antagonist on retinal pigment epithelium cells","volume":"54","author":"Sugita","year":"2013","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1136\/bjophthalmol-2015-307213","article-title":"CFH Y402H polymorphism and the complement activation product C5a: Effects on NF-kappaB activation and inflammasome gene regulation","volume":"100","author":"Cao","year":"2016","journal-title":"Br. J. Ophthalmol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"860","DOI":"10.4049\/jimmunol.1103451","article-title":"A Role for the NF-\u03baB Pathway in Cell Protection from Complement-Dependent Cytotoxicity","volume":"189","author":"Gancz","year":"2012","journal-title":"J. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"9686","DOI":"10.1073\/pnas.1503535112","article-title":"Complement membrane attack complexes activate noncanonical NF-\u03baB by forming an Akt+NIK+ signalosome on Rab5+ endosomes","volume":"112","author":"Surovtseva","year":"2015","journal-title":"Natl. Acad. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.neuron.2014.11.018","article-title":"NFkappaB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer\u2019s disease","volume":"85","author":"Lian","year":"2015","journal-title":"Neuron"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1080\/1547691X.2017.1420712","article-title":"NF-\u03baB signaling pathway-enhanced complement activation mediates renal injury in trichloroethylene-sensitized mice","volume":"15","author":"Liu","year":"2018","journal-title":"J. Immunotoxicol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.preteyeres.2014.11.005","article-title":"Complement activation and choriocapillaris loss in early AMD: Implications for pathophysiology and therapy","volume":"45","author":"Whitmore","year":"2015","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Daugan, M.V., Revel, M., Thouenon, R., Dragon-Durey, M.A., Robe-Rybkine, T., Torset, C., Merle, N.S., Noe, R., Verkarre, V., and Oudard, S.M. (2021). Intracellular Factor H Drives Tumor Progression Independently of the Complement Cascade. Cancer Immunol. Res.","DOI":"10.1158\/2326-6066.CIR-20-0787"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Song, C., Mitter, S.K., Qi, X., Beli, E., Rao, H.V., Ding, J., Ip, C.S., Gu, H., Akin, D., and Dunn, W.A. (2017). Oxidative stress-mediated NFkappaB phosphorylation upregulates p62\/SQSTM1 and promotes retinal pigmented epithelial cell survival through increased autophagy. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0171940"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Saddala, M.S., Lennikov, A., Mukwaya, A., and Huang, H. (2020). Transcriptome-Wide Analysis of CXCR5 Deficient Retinal Pigment Epithelial (RPE) Cells Reveals Molecular Signatures of RPE Homeostasis. Biomedicines, 8.","DOI":"10.3390\/biomedicines8060147"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1039\/C7FO01958K","article-title":"Quercetin-3-O-\u03b1-l-arabinopyranoside protects against retinal cell death via blue light-induced damage in human RPE cells and Balb-c mice","volume":"9","author":"Kim","year":"2018","journal-title":"Food Funct."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1016\/j.immuni.2013.10.018","article-title":"Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation","volume":"39","author":"Liszewski","year":"2013","journal-title":"Immunity"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Pang, Z., Chong, J., Li, S., and Xia, J. (2020). MetaboAnalystR 3.0: Toward an Optimized Workflow for Global Metabolomics. Metabolites, 10.","DOI":"10.3390\/metabo10050186"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8727\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:45:51Z","timestamp":1760165151000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8727"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,13]]},"references-count":69,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22168727"],"URL":"https:\/\/doi.org\/10.3390\/ijms22168727","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.04.19.440385","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,13]]}}}