Macrophages and neurons are targets of retinoic acid signaling after spinal cord contusion injury

Abstract

The physiological reactions after spinal cord injury are accompanied by local synthesis of the transcriptional activator retinoic acid (RA). RA exerts its effects by binding to retinoic acid receptors (RAR) which heterodimerize with retinoid X receptors (RXR) and then act as ligand-activated transcription factors. To identify possible cellular targets of RA we investigated protein levels and cellular distribution of retinoid receptors in the rat spinal cord at 4, 7, 14 and 21 days after a contusion injury. In the nonlesioned spinal cord, immunoreactivity for RARalpha, RXRalpha, RXRbeta and RXRgamma was localized in the cytosol of neurons, that of RXRalpha and RXRbeta in astrocytes and that of RARalpha, RXRalpha and RXRgamma in some oligodendrocytes. After contusion injury RARalpha and all RXRs appeared in the cell nuclei of reactive microglia and macrophages. This nuclear staining began at 4 days, was most prominent at 7 and 14 days and had decreased at 21 days after injury. A similar nuclear translocation was also observed for the RARalpha, RXRalpha and RXRbeta staining in neurons situated around the border of the contusion. These observations suggest that RA participates as a signal for the physiological responses of microglia and neurons after CNS injury.

Activated microglia modulate astroglial enzymes involved in oxidative and inflammatory stress and increase the resistance of astrocytes to oxidative stress in Vitro

“…Reduction of Sod2 activity accelerates the onset of Alzheimer's disease-like pathology in amyloid precursor protein transgenic mice (Esposito et al, 2006). After spinal cord contusion injury retinoic acid and it receptors are upregulated in glial and neuronal cells (Schrage et al, 2006) and it has been documented that astroglial Ass expression is increased in Alzheimer's disease (Heneka et al, 2001).…”

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

“…There are 3 members in the RXR family (RXRα, RXRβ, and RXRγ) that form homodimers or heterodimers with other nuclear receptors, including retinoic acid receptors (RAR), thyroid hormone receptors, vitamin D receptors (VDR), peroxisome proliferator activator proteins (PPAR), and liver X receptors (LXR), to control transcription of target genes. Following CNS injury, all 3 members of RXR are highly expressed in lesions [72]. We have recently found that RXRγ is highly expressed in oligodendrocyte lineage cells during the regenerative phase of CNS remyelination by using microarray analysis of the separate stages of CNS remyelination in rats.…”

Retinoic acid affects calcium signaling in adult molluscan neurons

“…Classically, RA influences gene expression by binding to nuclear hormone receptors, of which there are two main classes: the RA receptors (RARs) and retinoid X receptors (RXRs). A number of recent studies have, however, shown nonnuclear localization of RARs and RXRs (Carter et al 2010(Carter et al , 2011Maghsoodi et al 2008;Schrage et al 2006), and others have described nongenomic actions of the retinoid receptors Carter et al 2010;Liao et al 2004;Liou et al 2005;Poon and Chen 2008;Sarti et al 2012Sarti et al , 2013. Many of these studies described relatively rapid responses to RA, further supporting its role in nongenomic signaling.…”