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William C. Gordon, Eric J. Knott, Kristopher G. Sheets, Cornelius E. Regan, Jr., Nicolas G. Bazan; Müller Cell Reactive Gliosis Contributes To Retinal Degeneration In Ccl2-/-/Cx3cr1-/- Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1375.
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It has been reported that Ccl2-/-/Cx3cr1-/- mice exhibit retinal pathologies of human eye diseases, including abnormal RPE, drusen-like accumulation, photoreceptor degeneration, and choroidal neovascularization. The Ccl2 gene encodes the pro-inflammatory chemokine CCL2, which is responsible for chemotactic recruitment of monocyte-derived macrophages. The Cx3cr1 gene encodes the fractalkine receptor, CX3CR1, and is required for accumulation of monocytes recruited via CCL2. Proper secondary chemokine signaling from RPE, Müller glia, and astrocytes, is necessary to regulate the passage of leukocytes through the Blood Retina Barrier (BRB). Müller glial cells, contribute to the BRB, regulate leukocyte entry, and have been identified as the source of VEGF responsible for neovascularization and leakage. The purpose of this study was to test the hypothesis that Ccl2-/-/Cx3cr1-/--mice exhibit early Müller cell reactive gliosis in association with the onset and development of retinal lesions.
Ccl2-/-/Cx3cr1-/- mice were bred in LSUHSC animal care facility. Ccl2-/-/Cx3cr1-/- animals of 3 and 6 months were sacrificed and eyes enucleated. Eyes were collected for western blots, immunohistochemistry (IHC), and histology. Blots and sections were stained for Glial Fibrillary Acidic Protein (GFAP) and glutamine synthetase (GS).
By high resolution microscopy, lesions exhibit distinct boundaries in the ONL, matching the diameter of single Müller cells. The outer limiting membrane is discontinuous within lesions. Western blot analysis reveals upregulation of GFAP and decreased GS expression at 3 and 6 months, as compared to wild-type controls. Immunofluorescence demonstrates GFAP labeling within lesions but absence of GS. Noteably, GFAP labeling was found in prelesion areas.
Reactive Müller cell gliosis is associated with many retinal degenerative diseases. In this study, early Müller cell activation occurs within narrow columns that subsequently transform into lesions, suggesting that Müller cell reactive gliosis contributes to retinal degeneration in the Ccl2-/-/Cx3cr1-/- mouse.
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