Age-dependent development of retinal microgliopathy in LysM^Cre/+SOCS3^fl/flCX3CR1^gfp/gfp mice

Abstract

Purpose : Uncontrolled microglial activation is known to play a pathogenic role in degenerative retinal diseases, although the underlying mechanism remains poorly defined. Microglia can be activated by cytokines and its activation is negatively regulated by the chemokine CX3CL1/CX3CR1 pathway. We generated a LysM^Cre/+SOCS3^fl/flCX3CR1^gfp/gfp mouse line, where the suppressor of cytokine signaling 3 (SOCS3) was deleted in myeloid cells and CX3CR1 was replaced with green fluorescent protein (gfp). The aim of this study was to examine the influence of the SOCS3/CX3CR1 deletion on retinal microglial activation and neuronal degeneration during aging.

Methods : The lifespan of LysM^Cre/+SOCS3^fl/flCX3CR1^gfp/gfp mice was 12-15 months. Young (3-5 months old) or aged (10-12 months old) SOCS3^fl/fl, LysM^Cre/+SOCS3^fl/fl, Cx3cr1^gfp/gfp and LysM^Cre/+SOCS3^fl/flCx3cr1^gfp/gfp mice (N≥4) were used in the study. Retinal lesions were monitored by Micron IV and optical coherence tomography (OCT). Microglial activation was examined by confocal microscopy of retinal and RPE/choroidal flat-mounts. Retinal neurons were evaluated by immunohistochemistry on retinal sections.

Results : Multiple patches of retinal atrophy located at the outer retinal layers on OCT examination were observed in 75% of aged LysM^Cre/+SOCS3^fl/flCx3cr1^gfp/gfp mice. No fundus abnormality was observed in other strains of mice of the same age. Immunohistochemistry revealed discrete areas of RPE dysmorphology and degeneration of retinal neurons, including photoreceptors (p=0.0105 for cell number and p=0.0176 for outer segment length) and bipolar cells (p< 0.0001) in aged LysM^Cre/+SOCS3^fl/flCx3cr1^gfp/gfp mice, accompanied by microglial activation (p< 0.0001) and sub-retinal accumulation (p< 0.0001).

Conclusions : The LysM^Cre/+SOCS3^fl/flCx3cr1^gfp/gfp mice age-dependently developed retinal neuronal and RPE degeneration due to uncontrolled microglial activation. The mouse line is a good model of retinal microgliopathy.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.