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Wenxin Ma, Lian Zhao, Robert N Fariss, Wai T Wong; Age-related Changes in Microglial Signaling in the Aging Retina: Potential Role of CXCL13. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2262.
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Age-related retinal diseases, including AMD and diabetic retinopathy, involve neuroinflammation, indicating a role for immune dysregulation in their pathogenesis. Retinal microglia, the resident immune cell type, demonstrate multiple aging changes which may relate to age-related immune dysfunction. We explore the potential of CXCL13, an aging-regulated microglial cytokine, to drive pathologically-significant cell-cell interactions in the aging retina.
CXCL13 mRNA expression was monitored by qPCR and microarray analyses, while protein expression was measured with ELISA. Localization of CXCL13 and CXCR5 in the aged retina was analyzed by immunohistochemistry. A human RPE cell line (ARPE19) was used to evaluate CXCL13-CXCR5 signaling in RPE cells.
Microarray gene profiling demonstrated that CXCL13 mRNA expression increased monotonically as a function of advancing age in retinal microglia. Age-related increases in CXCL13 expression was verified on the mRNA level by qRT-PCR in retinal microglia isolated ex vivo by flow-cytometry, and on the protein level by ELISA in retinal cell lysates. Immunohistochemical analyses demonstrated that while microglia in the young (2 month-old) retina were immunonegative for CXCL13, those in aged (20 month-old) retina, located in the OPL, IPL, and subretinal space, were immunopositive. A small subpopulation of AP2α-positive amacrine cells in the INL were also immunopositive in both young and aged retina. Microglial expression of CXCL13 was found to increase with (1) retinal inflammation, as induced by intravitreal LPS, and (2) with retinal degeneration in 10-month old rd8/rd8 mice. CXCR5, the cognate receptor of CXCL13, was found constitutively expressed in RPE cells at the basal and lateral cell membranes and in αSMA+ smooth muscle cells in retinal and choroidal blood vessels. Exogeneous application of CXCL13 to ARPE19 cells increased in ARPE19 cells the expression of pro-inflammatory mediators, IL1β and TNFα, as well as markers of epithelial-to-mesenchymal transformation (EMT), snail, twist, and αSMA.
CXCL13 is a microglial-derived cytokine whose expression increases in an aging-dependent manner and which can mediate abnormal microglia-RPE signaling in the aged retina. These interactions may induce changes in RPE cells and alterations in the retinal immune environment in ways relevant to AMD pathogenesis.
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