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Through their ligand-activated heterodimeric complexes, RXRs regulate transcription of genes that play critical role in cellular differentiation and metabolic processes including lipid and glucose metabolism in neurons [2, 3, 8]. RXR ligands such as bexarotene or honokiol have been extensively studied and demonstrated to exhibit neuroprotective effects in animal models of glaucoma, Alzheimer disease (AD), and Parkinson disease (PD) [9,10,11,12]. The receptors are also implicated in microglial activation to protect tissues against neuroinflammatory response and mediate clearance of debris in multiple sclerosis (MS) and brain stroke pathology although involvement of specific homo- or heterodimers with other partners need to be further investigated [13, 14]. This diverse RXR functional spectrum is attributed to the fact that RXRs are positioned centrally in the nuclear receptor signalling network interacting directly and indirectly with transcriptional machinery frequently in a ligand-dependent manner [3]. As our understanding of RXRs and their heterodimers in regulating transcription, homeostasis, neuronal differentiation, neuroinflammation, and neuroprotective effects has expanded in recent years, RXRs have emerged as a promising therapeutic target in neurological disorders. This review discusses our current understanding of the structure, ligands, interactions, and functions of RXR. We also discuss the involvement of RXRs in various neuronal disorders and the potential therapeutic prospects of modulating the receptor function. The review closes with a brief discussion of on-going clinical trials and provides future perspectives of RXR and its partners in neurological research.
Schematic representation of RXR and its partners in reducing neuronal stress and neuroinflammatory effects: RXR stimulation by exogenous ligand bexarotene reduces the endoplasmic reticulum stress markers p-PERK and GADD153 in retinal ganglion cells and supresses BAD protein activation (1). Activation of the RXRα/PPARγ heterodimer with ligands activates proteins UCP2, eNOS, and MnSOD to reduce mitochondrial stress (2). The RXRα heterodimer regulates transcription of β-catenin (3). LG268 and bexarotene binds to RXRα/PPARα/β and Nurr1 forming a heterodimer complex that inhibits TNF-α, IL-1β, and IL6 and promotes NF-κB anti-inflammatory effects in microglia and macrophages (4, 5). A PPARγ-coactivator-1α (PGC-1α) reduces expression of BACE-1, a β-amyloid (Aβ) precursor protein cleaving enzyme (6). PPARγ increases the expression antioxidants GSH, NRF2, and Bcl-2 to play a protective role against apoptosis (7)
RXR heterodimerisation with PPAR, LXR, and Nurr1 also plays a role in regulating adaptive immune response and macrophage, monocyte, dendritic cell, and T cell functions through clearance of dead cells, T cell differentiation, and regulating gene repression of inflammatory mediators [101, 102]. Nurr1 was demonstrated to inhibit pro-inflammatory genes in LPS treated astrocytic and microglial cultures through NF-κB modulation [103] (Fig. 2 (4)). RXRα independently and in RXR/PPARδ complex influences innate inflammatory response by modulatory effects on cytokine and chemokine expression in myeloid cells and monocytes/macrophages [104, 105] (Fig. 2 (5)). Similar inhibition of the pro-inflammatory cytokines achieved through activation of LXR/RXR, PPARα/RXRα, and STAT3 pathways in inflammation-induced corneal angiogenesis has been reported to impart protection against inflammatory changes in rat cornea [106]. Baicalein (5,6,7-trihydroxyflavone), a flavonoid, was shown to enhance the PPARδ expression in brain microglia and suppress MAPK and NF-κB signalling resulting in augmentation of anti-inflammatory effects [107]. Similar attenuation of the neuroinflammation mediated by bexarotene has been implicated in rat model of subarachnoid haemorrhage [108]. These anti-inflammatory actions were shown to be mediated through its regulatory effects on PPARγ, SIRT6, and FoxO3A [108]. In addition, PPARγ-coactivator-1α (PGC-1α) which is a co-factor for transcription was implicated in the amelioration of microglial activation and reduced expression of amyloid precursor protein cleaving enzyme (BACE1) in APP23 AD mouse model [109, 110] (Fig. 2 (6)). RXR-activated PPARγ regulates oxidative stress response and prevents autophagy in association with increased expression of NRF2 in vivo in status epilepticus (SE) [111]. It was shown that PPARγ/RXR complex upon binding to its agonist rosiglitazone provided significant protection against hippocampal neuronal loss in epileptic rat model, attributed to enhanced expression of antioxidant GSH [111, 112] (Fig. 2 (7)). The overexpression of the PPARγ also led to increased expression of anti-apoptotic protein Bcl-2, leading to mitochondrial stabilisation in hippocampal neurons in vivo [113, 114]. Collectively, there is ample evidence to support the involvement of PPARγ in neuroprotection upon heterodimer formation with RXR [115]; however, direct RXR role in imparting neuroprotection in hippocampal and glial cells remains to be established.
Next-generation sequencing approaches deployed to dissect the role of RXR in regulating early neural differentiation and specification have led to the identification of RARγ, LXRβ, and RXRβ as abundantly expressed in undifferentiated embryonic stem cells (ESCs) [127, 128]. Studies have revealed that ligand-dependent activation of RAR/RXR is a dominant inducer of early neurogenesis, while LXR/RXR activation effects are largely limited to early differentiation phases [129]. Accordingly, LXR synthetic agonist GW3965/LG268 demonstrated remarkable impact on cell fate specification of the neuronal progenitors, initiating axonal guidance and neurogenesis [129]. The effects of RXR-mediated signalling on mouse oligodendrocyte differentiation were also suggested by an almost complete differentiation block induced in oligodendrocyte precursor cells that lack RXRγ [130]. In rodents, lysolecithin-induced demyelination of brain slices was associated with the upregulation of RXRγ in the cytoplasm of oligodendrocyte lineage cells [14]. Treatment with 9-cis-RA during remyelination process promoted oligodendrocyte differentiation and myelin repair in RXRγ-dependent manner in vivo [14]. These findings have not only established RXR role in mediating cell differentiation but also highlight RXR functions beyond the nucleus depending on physiological state of the cell [14]. Further, 9-cis-RA-induced RXRγ activation is believed to suppress inhibiting factors of the oligodendrocyte differentiation such as LINGO-1, CSPGs, hyaluronic acid, and Wnt/β-catenin signalling resulting in OPC maturation [131] (Fig. 4B). RXR signalling may also be relevant for neuroprotective effects on dopaminergic (DA) neurons. RXR heterodimeric partner Nurr1 is expressed in developing and mature DA neurons in several regions of the brain including the hippocampus and cerebral cortex [11]. Nurr1 and other homologous members NGFIB and Nor1 can be activated by hypoxic/ischemic stress and kainic acid-induced excitotoxicity, and its association with RXR can be neuroprotective for DA neuronal cells [80]. It has been demonstrated that Nurr1 agonist mercaptopurine (6-MP) stimulates Nurr1 by direct binding to its N-terminal AF-1 domain [132]. Treatment with 6-MP was shown to reduce the cerebral infarct in a rodent-permanent middle cerebral artery occlusion (pMCAO) model and lead to reduced inflammatory cytokines IL-1β and TNF-α in the serum and CSF [132]. These observations collectively implicate the role of RXR and its partners in regulating neuronal differentiation and mediating neuroprotective effects.
RXR via heterodimerisation with PPARγ plays crucial role in mediating glycaemic control and regulating cellular and biochemical effects of insulin actions [78]. 9-cis-RA concentrations in different feeding, fasting, and glucose challenge conditions to the rodents were inversely associated with a decrease in insulin levels [53]. Glucose utilisation by all cell types fluxes through major pathways in excitatory and inhibitory neurons and astrocytes, via glucose transporters GLUT4 and GLUT3 [133, 134]. RXR participates in adipogenesis by regulating early aspects of GLUT4 responsible for linking adipogenesis to subsequent events of lipid metabolism [135]. RXR agonist, LG268, and PPARγ agonist, rosiglitazone, were shown to generate insulin sensitisation in rodent model of type 2 diabetes via overlapping mechanisms [93, 136]. Similar effects of rosiglitazone and LG268 were identified on the metabolic gene expression in white adipose tissue of skeletal muscle and liver in Zucker diabetic fatty rat models [137]. Rosiglitazone activation led to decreased mRNA expression of the TNF-α in adipose tissue [138]. Further, while rosiglitazone treatment induced mRNA expression of GLUT4, mitochondrial carnitine palmitoyl-transferase (MCPT), stearoyl CoA desaturase 1 (SCD1), and CD36, antagonistic or nil effects were observed upon RXR agonist, LG268 treatment [136, 137] (Fig. 5). In contrast, RXR agonist increased the expression of MCPT, SCD1, and CD36 in the liver, whereas rosiglitazone treatment only enhanced the expression of CD36 [136]. This differential regulation of genes in adipose and liver tissues is reflective of the fact that insulin sensitisation may be accomplished by multiple mechanisms [136]. In addition, the anti-diabetic effects of RXR agonist may not simply be a reflection of RXR/PPARγ activation, and that permissiveness with interaction partners can vary within different cell and tissue types [136].
Cumulative evidence of RXR roles in mediating Aβ clearance, inducing microglial activation and remyelination in different neurological disorders, has generated interest in greater understanding of the RXR signalling in neuronal tissues [11, 68, 139]. The use of RXR agonists and antagonists may help achieve specific modulation of target genes and biochemical networks, which may serve as a promising therapeutic target [48]. A schematic representation of RXR roles and implications of its direct or indirect activation via heterodimer formation and pharmacological stimulation in neurodegenerative diseases is summarised in Fig. 6. 153554b96e
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