Rcor2 underexpression in senescent mice: a target for inflammaging?

Abstract

BackgroundAging is characterized by a low-grade systemic inflammation that contributes to the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD). However, little knowledge is currently available on the molecular processes leading to chronic neuroinflammation. In this context, recent studies have described the role of chromatin regulators in inflammation and longevity including the REST corepressor (Rcor)-2 factor, which seems to be involved in an inflammatory suppressive program.MethodsTo assess the impact of Rcor2 in age-related inflammation, gene expression levels were quantified in different tissues and ages of the spontaneous senescence-accelerated P8 mouse (P8) using the SAMR1 mouse (R1) as a control. Specific siRNA transfection in P8 and R1 astrocyte cultures was used to determine Rcor2 involvement in the modulation of neuroinflammation. The effect of lipopolysaccharide (LPS) treatment on Rcor2 levels and neuroinflammation was analyzed both in vivo and in vitro.ResultsP8 mice presented a dramatic decrease in Rcor2 gene expression compared with R1 controls in splenocytes, an alteration also observed in the brain cortex, hippocampus and primary astrocytes of these mice. Rcor2 reduction in astrocytes was accompanied by an increased basal expression of the interleukin (Il)-6 gene. Strikingly, intraperitoneal LPS injection in R1 mice downregulated Rcor2 in the hippocampus, with a concomitant upregulation of tumor necrosis factor (Tnf-α), Il1-β and Il6 genes. A negative correlation between Rcor2 and Il6 gene expression was also verified in LPS-treated C6 glioma cells. Knock down of Rcor2 by siRNA transfection (siRcor2) in R1 astrocytes upregulated Il6 gene expression while siRcor2 further increased Il6 expression in P8 astrocytes. Moreover, LPS activation provoked a further downregulation of Rcor2 and an amplified induction of Il6 in siRcor2-tranfected astrocytes.ConclusionsData presented here show interplay between Rcor2 downregulation and increased inflammation and suggest that Rcor2 may be a key regulator of inflammaging.

Environmental Enrichment Improves Behavior, Cognition, and Brain Functional Markers in Young Senescence-Accelerated Prone Mice (SAMP8)

“…These mice exhibited cognitive and emotional disturbances from young ages, probably due to brain pathological hallmarks such as OS, inflammation, and activated neuronal death pathways, mainly affecting cortex and hippocampus. Molecular changes at young ages are based on cerebral and cognitive dysfunction in SAMP8 [38].…”

Understanding Epigenetics in the Neurodegeneration of Alzheimer’s Disease: SAMP8 Mouse Model

“…Phenotypical traits of inflammaging with higher expression of inflammatory mediator molecules were found in the SAMP8 hippocampus at an early age of 2 months [ 24 ]. There was also an increased response to acute inflammatory injuries at 3 months of age in SAMP8 compared to SAMR1, as detected by the levels of circulating proinflammatory cytokines [ 227 ]. Inflammation was also detected in peripheral tissues such as liver [ 228 ].…”

Transcriptomic Features of T Cell-Barren Tumors Are Conserved Across Diverse Tumor Types

“…RCOR2 was ranked in the 99th percentile (by LFC method) in 12 of 23 tumor types. RCOR2 encodes a nuclear transcriptional corepressor that promotes the epigenetic silencing of gene transcription in neural stem cells (37) and suppresses the production of proinflammatory cytokines in a mouse model of aging (63). Moreover, RCOR2 binds and activates LSD1, a histone lysine demethylase recently identified as a potent inhibitor of anti-tumor immunity (37,38).…”