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Aldose reductase mediates retinal microglia activation
Kun-Che Chang1, Biehuoy Shieh1, J Mark Petrash1
1Department of Ophthalmology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
Abstract:
Retinal microglia (RMG) are one of the major immune cells in charge of surveillance of inflammatory responses in the eye. In the absence of an inflammatory stimulus, RMG reside predominately in the ganglion layer and inner or outer plexiform layers. However, under stress RMG become activated and migrate into the inner nuclear layer (INL) or outer nuclear layer (ONL). Activated RMG in cell culture secrete pro-inflammatory cytokines in a manner sensitive to downregulation by aldose reductase inhibitors. In this study, we utilized CX3CR1(GFP) mice carrying AR mutant alleles to evaluate the role of AR on RMG activation and migration in vivo. When tested on an AR(WT) background, IP injection of LPS induced RMG activation and migration into the INL and ONL. However, this phenomenon was largely prevented by AR inhibitors or in AR null mice, or was exacerbated in transgenic mice that over-express AR. LPS-induced increases in ocular levels of TNF-α and CX3CL-1 in WT mice were substantially lower in AR null mice or were reduced by AR inhibitor treatment. These studies demonstrate that AR expression in RMG may contribute to the proinflammatory phenotypes common to various eye diseases such as uveitis and diabetic retinopathy.
Insights
Aldose reductase (AR) inhibitors can prevent retinal microglia activation and migration, crucial for inflammatory eye diseases like uveitis and diabetic retinopathy. This research highlights AR
Area of Science:
- Ophthalmology
- Immunology
- Cell Biology
Background:
- Retinal microglia (RMG) are key immune cells in the eye, monitoring for inflammation.
- Under stress, RMG activate, migrate to different retinal layers, and secrete pro-inflammatory cytokines.
- Aldose reductase (AR) inhibitors show potential in downregulating RMG pro-inflammatory activity.
Purpose of the Study:
- To investigate the role of aldose reductase (AR) in retinal microglia (RMG) activation and migration in vivo.
- To evaluate the therapeutic potential of AR inhibition in inflammatory eye conditions.
Main Methods:
- Utilized CX3CR1(GFP) mice with AR mutant alleles to study AR's function in RMG.
- Administered LPS to induce inflammation and observed RMG activation and migration.
- Assessed ocular levels of pro-inflammatory cytokines like TNF-α and CX3CL-1.
Main Results:
- LPS induced RMG activation and migration in wild-type mice.
- AR inhibitors, AR null mice, or reduced AR expression largely prevented LPS-induced RMG activation and migration.
- AR overexpression exacerbated RMG activation and migration.
- AR inhibition or deficiency significantly reduced ocular TNF-α and CX3CL-1 levels.
Conclusions:
- Aldose reductase (AR) plays a significant role in activating and migrating retinal microglia (RMG).
- AR expression in RMG may contribute to the inflammatory processes in eye diseases such as uveitis and diabetic retinopathy.
- Targeting AR could be a potential therapeutic strategy for managing ocular inflammation.
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