Retinal Phenotype following Combined Deletion of the Chemokine Receptor CCR2 and the Chemokine CX3CL1 in Mice

Abstract

Purpose: Conflicting data were reported with respect to the retinal phenotype of mice with dual perturbation of the CCL2 and CX3CR1 genes. We report the generation and retinal phenotype of mice with a reverse CCR2/CX3CL1 gene deficiency as a suggested model for age-related macular degeneration (AMD). Methods: Crossing of single-deficient mice generated CCR2/CX3CL1 DKO mice. DKO mice were compared with age-matched C57BL6J mice. Evaluation included color fundus photographs, electroretinography (ERG), histology and morphometric analysis. Immunohistochemistry for CD11b in retinal cross-sections and retinal pigment epithelium (RPE)-choroid flat mounts was performed to assess microglia and macrophage recruitment. Results: A minority of DKO mice showed yellowish subretinal deposits at 10 months. ERG recordings showed reduced cone sensitivity in young, but not older DKO mice. Compared to wild-type mice, DKO mice exhibited 11% reduction in the number of outer nuclear layer nuclei. Old DKO mice had an increased number of CD11b-positive cells across the retina, and on RPE-choroid flat mounts. Conclusions: In the absence of the rd8 allele, deficiency of CCR2 and CX3CL1 in mice leads to a mild form of retinal degeneration which is associated with the recruitment of macrophages, particularly to the subretinal space. This model enables to assess consequences of perturbed chemokine signaling, but it does not recapitulate cardinal AMD features.

Risk factors and biomarkers of age-related macular degeneration

“…However, these symptoms may have been exacerbated by the presence of an rd8 mutation in the genetic background of the mice studied, without which, a mild phenotype indicative of some retinal stress was observed (Vessey et al, 2012). In the absences of the rd8 allele, deficiency in CCR2 in mice was found to lead to a mild form of retinal degeneration which is associated with the recruitment of macrophages, particularly to the subretinal space; though this model enabled the research group to assess consequences of perturbed chemokine signaling, it did not recapitulate cardinal AMD features (Hagbi-Levi et al, 2016). CCL2 expression by retinal Mueller cells promotes macrophage infiltration of the retina and accelerates retinal damage and photoreceptor death, following injury (Rutar et al, 2012).…”

Amount of Mononuclear Phagocyte Infiltrate Does Not Predict Area of Experimental Choroidal Neovascularization (CNV)

“…Ccl2 genetic deletion has variable ophthalmic effects, including protection and accelerated degeneration of the retina, as well as reduction in angiogenesis. 33–36 Increased intraocular Ccl2 has been reported in geographic atrophy and nv AMD patients, 37 and increased subretinal infiltration of Ccr2 + cells has been observed in patients. 35 …”