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Jun Yamada, Hiroki Hatanaka, kazuko asada, Kana Nakata, Junji Hamuro, Shigeru Kinoshita; The role of cell senescence, Epithelial-Mesenchymal Transition, and fibrosis in the generation of vicious inflammatory cycle between macrophages and retinal pigment epithelium. Invest. Ophthalmol. Vis. Sci. 2013;54(15):360.
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© ARVO (1962-2015); The Authors (2016-present)
Macrophages (Mps) and retinal pigment epithelium cells (RPE) are the two major players dictating the diverse stages of pathological inflammation involved in age-related macular degeneration (AMD). Recently it has become evident that Mps and RPE cells are composed of distinctly activated populations. The purpose of this study was to report the mutual interplay between Mps and RPE cells in the production of cytokines generating the vicious inflammatory cycle.
The oxidized LDL (ox-LDL) or TNF-α induced production of MCP-1, IL-6 and VEGF. RPE-cell fibrosis induced by TGF-β +/− TNF-α and the phagocytic activity of RPE cells were evaluated. GRA12228 and the histone deacetylase (HDAC) inhibitor OBP-801, which selectively act on Mps population distinct in their intracellular redox status, were evaluated for their blocking activity in the induction of the cytokines described above and RPE-cell fibrosis.
Gene signatures of ARPE19 exposed to TGF-β +/− TNF-α revealed elevation of collagen 1A, 3A, fibronectin, snail, wnt5A, wnt5B and IL-1α, and VEGF-A. TGF-β +TNF-α skewed the intracellular redox state of ARPE19 to oxidative state and induced the synergistic elevation of VEGF-A production. Interestingly MCP-1 production was reduced by exposure to ox-LDL of murine primary RPE cells co-cultured with Mps, while not by LDL, yet production of both VEGF-A and IL-6 were augmented by ox-LDL, but not by LDL. TGF-β induced fibrosis, a typical pathological feature of the oxidative state of RPE cells. GRA12228, inhibiting TNF-α production by Mps, subsequently inhibited VEGF-A production to prevent formation of the vicious cycle of inflammation. OBP-801 (5nM) dramatically prevented RPE-cell fibrosis.
Gene-signature features induced by TGF-β+/-TNF-α implicate crucial roles of these cytokines in phase transition, such as epithelial-mesenchymal transition, cell senescence, and fibrosis. The vicious cycle of inflammation and the resultant RPE-cell fibrosis might be responsible for the interplay between Mps and RPE cells mediated by MCP-1, VEGF-A, IL-6, TGF-β, and TNF-α. All of these pathological features might be finely tuned by the intracellular redox status of Mps and RPE.
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