The Nuclear Receptor Nurr1 Modulates the Expression and Activity of <scp>PPARγ</scp> in Human Pro‐Inflammatory Macrophages

Nurr1 is a member of the nuclear receptor family NR4A that modulates inflammation typically by inhibiting the NF-κB signalling pathway. In vitro, Nurr1 can interact with the peroxisome proliferator-activated receptor (PPAR)γ, as well as be recruited to the Pparg promoter in microglial cells; however, their functional relationship is not established. Here, we aimed to investigate the role of Nurr1 on PPARγ activity in human macrophages. Blood monocytes were cultured with GM-CSF or M-CSF to generate pro- (GM-MDMs) and anti-inflammatory (M-MDMs) macrophages, respectively. The protein levels of PPARγ and Nurr1 were elevated in GM-MDMs compared to M-MDMs, and their expression was positively correlated. PPARγ activation in GM-MDMs with the agonist rosiglitazone did not modify Nurr1 expression. However, Nurr1 activation with the agonist C-DIM12 increased PPARγ levels through protein stabilisation. Further, agonistic activation of Nurr1 decreased the proportion of PPARγ molecules phosphorylated at Ser84, which is a repressive mark for PPARγ transcriptional activity. Accordingly, exposure of GM-MDMs to C-DIM12 enhanced the expression of two PPARγ target genes induced by rosiglitazone, CD36 and PLIN2. Both PPARγ and Nurr1 agonists exhibited anti-inflammatory effects on LPS-stimulated GM-MDMs when administered alone, but C-DIM12 did not globally increase the effectiveness of rosiglitazone under that condition. These findings suggest that Nurr1 enhances PPARγ transcriptional activity, potentially through stabilising PPARγ protein levels and decreasing its repressive phosphorylation at Ser84. This novel mechanism highlights the role of Nurr1 in targeting not only inflammation but additional pathways regulated by PPARγ in macrophages.