Nuclear receptors of NR1 and NR4 subfamilies in the regulation of microglial functions and pathology

Abstract

This review provides an overview of researches on the NR1 and NR4 nuclear receptors involved in the regulation of microglial functions. Nuclear receptors are attractive candidates for drug targets in the therapies of the central nervous system disorders, because the activation of these receptors is expected to regulate the functions and the phenotypes of microglia, by controlling the expression of specific gene subsets and also by regulating the cellular signaling mechanisms in a nongenomic manner. Several members of NR1 nuclear receptor subfamily have been examined for their ability to regulate microglial functions. For example, stimulation of vitamin D receptor inhibits the production of pro‐inflammatory factors and increases the production of anti‐inflammatory cytokines. Similar regulatory actions of nuclear receptor ligands on inflammation‐related genes have also been reported for other NR1 members such as retinoic acid receptors, peroxisome proliferator‐activated receptors (PPARs), and liver X receptors (LXRs). In addition, stimulation of PPARγ and LXRs may also result in increased phagocytic activities of microglia. Consistent with these actions, the agonists at nuclear receptors of NR1 subfamily are shown to produce therapeutic effects on animal models of various neurological disorders such as experimental allergic encephalomyelitis, Alzheimer's disease, Parkinson's disease, and ischemic/hemorrhagic stroke. On the other hand, increasing lines of evidence suggest that the stimulation of NR4 subfamily members of nuclear receptors such as Nur77 and Nurr1 also regulates microglial functions and alleviates neuropathological events in several disease models. Further advancement of these research fields may prove novel therapeutic opportunities.

Transcriptional Regulation of the Synaptic Vesicle Protein Synaptogyrin-3 (SYNGR3) Gene: The Effects of NURR1 on Its Expression

“…Prostaglandin E1 (PGE1) and its dehydrated metabolite, PGA1 have been shown to exhibit neuroprotective effects in a NURR1-dependent manner via an enhancement of the expression of NURR1 target genes in mouse dopaminergic neurons [ 32 ]. Moreover, NURR1 has been shown to interact with NF-kappa B to suppress the inflammatory response in microglia [ 33 ]. NURR1 can be activated by numerous compounds, although originally it was thought to be a constitutive transactivating agent [ 34 ].…”

Neural ensembles that encode affective mechanical and heat pain in mouse spinal cord

“…We find increased expression of inflammatory cytokines in M1 micro-glia (including Il1b, Tnf, Il6 ) and downregulation of anti-in-flammatory Il10 . Interestingly, also M0 microglia displayed a range of gene expression changes including upregulation of the pro-inflammatory chemokines Ccl3, Ccl4 , inflammation-induced transcription factor Nr4a1 nuclear receptor which suppress expression of genes in the inflammatory NfkB pathway, as well as the NF-κB inhibitor-α ( Nfkbia ), which repress NF-κB and signalling 82,83 . Thus, there are molecular alterations of microglia which may contribute to the inflammatory state and hyperalgesia.…”

The Promotion of Humoral Immune Responses in Humans via SOCS1-Mediated Th2-Bias Following SARS-CoV-2 Vaccination

“…It has been reported that NR4A2-deficient T cells inhibit Foxp3 expression, leading to an abnormal induction of Th1 cells and aggravation of colitis [28]. Nevertheless, apart from its role in modulating Treg cell function, NR4A2 has also been shown to regulate vitamin D metabolism, Th17 cell differentiation, and microbiota homeostasis in some inflammatory autoimmune diseases, such as inflammatory bowel disease and Graves' diseases [59][60][61][62]. Thus, given the important regulatory roles of vitamin D, Th17, and the microbiota in inflammatory diseases, there may be other possible mechanisms underlying the observed modulatory effects of SOCS1/SOCS3 and NR4A2 on differential vaccination responses in this study, which deserve future study.…”