Activation of liver X receptor delayed the retinal degeneration of rd1 mice through modulation of the immunological function of glia

Abstract

Retinal degeneration (RD), including retinitis pigmentosa (RP), is an inherited eye disease characterized by progressive degeneration of photoreceptors. Recently, immune cells, including microglia, Müller cells and astrocytes, in degenerative retina are demonstrated to play key roles in the development of RD and can be used as potential therapeutic targets. Liver X receptors (LXRs) are important immuno-inflammatory response transcription factors that have been reported to be a new potential therapeutic drug target for neurodegenerative diseases. However, the potential therapeutic utility of LXRs for RP has not been evaluated. In the present study, Pde6β (rd1) mice received intraperitoneal injections of T0901317 (T0, 50 mg/kg/d) or vehicle (2% DMSO) for 7 days with age-matched C57/BL6 mice as controls. The effect of T0 was examined by quantitating photoreceptor apoptosis, microglial density and the expression of inflammatory mediators; the underlying mechanisms were then explored with a microarray assay. T0 markedly delayed apoptosis of the photoreceptors, partially through suppressing the activation of microglia and the gliosis of Müller cells, and decreased the expression levels of IL-6, iNOS, COX-2 and ENG in rd1 mice; as a result, the visual function of T0-treated rd1 mice measured with electroretinograms (ERG) was preserved for a longer time than that of vehicle-treated rd1 mice. The microarray assay showed that the Janus kinase/Signal Transducer and Activator of Transcription (JAK-STAT) signaling pathway was significantly affected in the retina of rd1 mice with T0 treatment. Our data suggested that T0 modulated the immunologic function of glia cells in the degenerative retina through the JAK3/STAT pathway and delayed the apoptosis of photoreceptors.

Luteolin Attenuates IL-1β-Induced THP-1 Adhesion to ARPE-19 Cells via Suppression of NF-κB and MAPK Pathways

“…In many retinal degenerative (RD) diseases, the pathogenesis is inflammation-induced, involving the recruitment and activation of microglia and macrophages, the expression of inflammatory mediators (COX-2 and iNOS), and photoreceptor cell death. The proinflammatory cytokine IL-1 β triggers inflammatory responses and attracts inflammatory cells to migrate into the retina, promoting retinal impairment and degeneration in RD diseases [ 38 , 39 ]. Numerous studies reported that IL-1 β activates the expression of other proinflammatory cytokines and modulates chemokine expression.…”

Autophagy: A Role in the Apoptosis, Survival, Inflammation, and Development of the Retina

“…Several neurodegenerative diseases, such as glaucoma and retinitis pigmentosa, have been reported to induce the reactive gliosis of Müller cells with a rapid and massive accumulation of glial fibrillary acidic protein (GFAP) [54][55][56]. GFAP is exclusively expressed in the end feet of Müller cells, and GFAP is a marker for Müller cell activation [57].…”

Silica nanoparticle exposure during the neonatal period impairs hippocampal precursor proliferation and social behavior later in life

“…RT-qPCR was performed as previously described. 15 In brief, total RNA was extracted from the hippocampus using Trizol (Thermo Fisher Scientific, Waltham, MA, USA) and was reverse transcribed according to the manufacturer's instructions. Quantitative PCR was then performed in triplicate with a CFX96 Real-time PCR System (BioRad) using SYBR Green qPCR Mix (Takara Bio Inc., Kusatsu, Japan).…”