title: Amyloid-β-induced matrix metalloproteinase-9 secretion is associated with retinal pigment epithelial barrier disruption.
abstract: Local and chronic inflammation induced by amyloid-β (Aβ) plays a central role in the development of age-related macular degeneration. The retina is an immune-privileged site due to local tissue barrier. Yet, the manner by which immune cells pass through this barrier and accumulate in the retina remains unclear. Matrix metalloproteinases (MMPs) induce barrier disruption via proteolysis of epithelial tight junction (TJ) proteins. We hypothesized that Aβ-induced MMP secretion causes disruption of epithelial barrier integrity. To test this hypothesis, human adult retinal pigment epithelial (haRPE) cells were exposed to Aβ, and the expression of MMP-2 and MMP-9 was detected using gelatin zymography. To demonstrate the key role of MMPs in modulating epithelial barrier structure, the MMP agonist 4-aminophenylmercuric acetate (APMA), an MMP inhibitor (GM6001) and siRNA against MMP-9 were employed for comparison. We found that MMP-9, secreted by Aβ- or APMA-stimulated cells, mediated low transepithelial electrical resistance (TER) and high transepithelial permeability by disrupting TJ proteins. However, these alterations were reduced by the MMP inhibitor GM6001 or by silencing of the MMP-9 gene. Our findings suggest that the degradation of TJ proteins such as zonula occludens-1, occludin and F-actin by MMP-9 secreted by Aβ-stimulated cells constitutes an important mechanism in the breakdown of the barrier which contributes to chronic inflammation in the retina of age-related macular degeneration.
authors.affiliation: Department of Ophthalmology, Shanghai Tenth People's Hospital affiliated with Tongji University, School of Medicine, Shanghai, P.R. 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
mesh_terms: D000328:Adult; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D010662:Phenylmercuric Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D020836:Protein Structure, Quaternary; D034741:RNA, Small Interfering / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D062725:Tight Junction Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C508606:CXCL8 protein, human; D004151:Dipeptides; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D034741:RNA, Small Interfering; D062725:Tight Junction Proteins; C010024:4-aminophenylmercuriacetate; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D010662:Phenylmercuric Acetate