title: Aβ-induced senescent retinal pigment epithelial cells create a proinflammatory microenvironment in AMD.
abstract: OBJECTIVE
  Chronic inflammation is implicated in the pathogenesis of AMD. The source of chronic inflammation is often attributed to the progressive activation of immune cells over time. However, recent studies have shown that senescent cells can alter tissue microenvironment via secretion of growth factors, proteases, and inflammatory cytokines and might be an additional source of chronic inflammation. We hypothesized that altered secretory pattern in Aβ-induced senescent RPE cells may contribute to compromised RPE barrier integrity and chronic inflammation in AMD.
  
  
  METHODS
  Senescence was assessed by measuring the SA-β-Galactosidase activity, the expressions of p16(INK4a) and ATM, and cell cycle analysis. Expressions of IL-8 and MMPs were analyzed by RT-PCR, ELISA, and gelatin zymography. The barrier structures of RPE cells were detected by actin-tracker, ZO-1, claudin-19, occludin immunochemistry, and Western blot; barrier function was analyzed by measuring transepithelial resistance (TER) and transepithelial diffusion rate of FITC-dextran. For inhibitory studies, MMP-9 was inhibited by RNA interference strategy.
  
  
  RESULTS
  Aβ promotes RPE cells to enter senescence and secrete higher concentrations of IL-8 and MMP-9. Secretion of MMP-9 is associated with compromised barrier integrity and with processing of IL-8 to a more activated form. Silence of MMP-9 preserved the barrier integrity of senescent RPE cells.
  
  
  CONCLUSIONS
  The altered secretory phenotype of senescent RPE cells may contribute to age-related inflammation in AMD. Chinese Abstract.
authors.affiliation: Department of Ophthalmology, Tenth People's Hospital, Affiliate of Tongji University, School of Medicine, Shanghai, China.
authors.forename: Lining
authors.initials: L
authors.lastname: Cao
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Ding
authors.initials: D
authors.lastname: Xu
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Chaoqi
authors.initials: C
authors.lastname: Liu
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D060833:Cellular Microenvironment / Q000276:immunology; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D002908:Chronic Disease; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005333:Fetus / Q000166:cytology; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D008268:Macular Degeneration / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D062793:Occludin / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity; D034741:RNA, Small Interfering / Q000235:genetics; D055213:Retinal Pigment Epithelium / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D012173:Retinitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C508606:CXCL8 protein, human; D016209:Interleukin-8; C568985:OCLN protein, human; D062793:Occludin; D010446:Peptide Fragments; D034741:RNA, Small Interfering; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; C075222:amyloid beta-protein (1-42); C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: age-related macular degeneration (AMD); amyloid-beta (Aβ); inflammation; senescence