Members of the NR4A family have been reported to both positively and negatively regulate pro-inflammatory genes (Bonta et al., 2006; Doi et al., 2008; Pei et al., 2006). The present studies demonstrate a potent anti-inflammatory activity of Nurr1 in microglia and astrocytes. We propose that this anti-inflammatory activity is mediated by a Nurr1/CoREST transrepression pathway that operates in a feedback manner to restore transcription of NF-κB target genes to a basal state (Fig. 7B). In this pathway, Nurr1 is recruited to NF-κB on inflammatory gene promoters dependent on GSK3β-mediated phosphorylation of S468 of p65. Nurr1 subsequently recruits the CoREST co-repressor complex in an NLK-dependent manner. Since HDAC1-mediated deacetylation is known to regulate the duration of p65 transcriptional activity, and HDAC1 is a component of the CoREST complex, the Nurr1-CoREST axis might have essential roles in terminating inflammatory responses by p65 clearance from the target promoters. These studies thus establish an unexpected biological role for the CoREST complex, previously considered to mainly be involved in the repression of neuronal genes in NSCs or non-neuronal cells (Ballas et al., 2005). We also
