Aldose reductase mediates retinal microglia activation

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 CX3CR1GFP mice carrying AR mutant alleles to evaluate the role of AR on RMG activation and migration in vivo. When tested on an ARWT 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.

Diabetes-Independent Retinal Phenotypes in an Aldose Reductase Transgenic Mouse Model

“…Elevated expression of AR has been associated with a shift toward a proinflammatory phenotype characterized by increased levels of activated retinal microglia [ 13 ]. Since activated retinal Müller glia suspected in our AR-Tg mice would be expected to secrete proinflammatory cytokines and chemokines, we looked for corollary signs of inflammation, such as increased levels of activated retinal microglia and astrocytes.…”

Nutraceutical effects of Emblica officinalis in age-related macular degeneration

“…Since retinal microglia are immune cells that mediate inflammatory responses in the eye, their activation causes secretion of pro-inflammatory cytokines thereby contributing to the pathogenesis of eye diseases. However, suppression of aldose reductase prevents retinal microglia activation and migration, subsequently preventing ocular inflammation and disease development [51].…”

Microglia at center stage: a comprehensive review about the versatile and unique residential macrophages of the central nervous system

“…Microglia research still relies heavily on in vivo [ 51 ] and ex vivo cellular and tissue models [ 241 ], including mouse [ 32 , 70 , 209 , 306 , 307 ], rat [ 308 ] and zebrafish [ 70 , 309 ], as these cells are unique and very different from other tissue macrophages and bone marrow derived cells. However, for research in humans, two in vitro approaches have been successfully envisaged: (1) isolation of primary microglia from surgical specimens of the brain [ 310 ] or post-mortem tissue samples [ 147 , 278 , 311 , 312 ], or (2) differentiation of microglia-like cells from embryonic stem cells [ 313 ], induced pluripotent stem cells (iPS) [ 314 – 316 ], bone marrow stem cells or blood monocytes [ 317 – 319 ].…”