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Wenxin Ma, Lian Zhao, Lijin Dong, Maria M Campos, Robert N Fariss, Wai T Wong; CXCL13, an aging-related microglial-derived cytokine, promotes epithelial-mesenchymal transformation (EMT) in RPE cells. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5375.
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© ARVO (1962-2015); The Authors (2016-present)
Age-related macular degeneration (AMD) has been associated with neuroinflammatory changes in the outer retina and as well as RPE disorganization that is evident as pigment clumping. Retinal microglia, the primary resident immune cell, demonstrate multiple aging changes, including changes in cytokine expression. In previous gene profiling experiments in retinal microglia, we had identified CXCL13 as a cytokine whose expression increased progressively with aging. As its cognate receptor, CXCR5, is expressed by RPE cells, we explored the ability of CXCL13 to drive interactions between microglia and RPE cells in ways potentially relevant to AMD pathogenesis.
RPE responses to recombinant CXCL13 stimulation were investigated using ARPE19 cells and mouse RPE-sclerochoroidal explants. A transgenic mouse model involving the use of a microglia-specific tamoxifen-inducible Cre recombinase (CX3CR1-CreER) was used to drive the overexpression of CXCL13 in microglia via a flox-STOP-flox-CXCL13 transgene. In vitro and in vivo responses were evaluated with rt-PCR, western blot and ELISA analyses, and immunohistochemistry.
In vitro CXCL13 stimulation of RPE cells in (1) the ARPE19 cell-line and (2) in RPE-sclerochoroidal explants increased mRNA and protein expression of epithelial-to-mesenchymal transformation (EMT) gene markers (snail1, vimentin, fibronectin) and decreased RPE-expressed genes such as ZO1 and RPE65. In transgenic mice, tamoxifen-induction resulted in increased CXCL13 mRNA expression in retinal microglia and increased CXCL13 protein levels in the retina. Increased CXCL13 expression in vivo was correlated with RPE changes including structural disorganization, decreased RPE65 expression, and increased EMT marker (snail1, vimentin, fibronectin) expression.
Increased CXCL13-CXCR5 signaling from microglia to RPE cells was associated with in vitro and in vivo RPE changes and disorganization resembling features observed in AMD. CXCL13-CXCR5 signaling may be a potential mechanism connecting aging-related immune changes to retinal degeneration in AMD.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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