Compensatory Expression of Nur77 and Nurr1 Regulates NF-κB–Dependent Inflammatory Signaling in Astrocytes

• DOI: 10.1124/mol.118.112631
• Publication Date: 2018-08-15T18:25:19Z
• Authors: Katriana A. Popichak; Sean L. Hammond; Julie A. Moreno; Maryam F. Afzali; Donald S. Backos; Richard D. Slayden; Stephen Safe; Ronald B. Tjalkens
• Keywords: Proinflammatory cytokine

Inflammatory activation of glial cells promotes loss dopaminergic neurons in Parkinson disease. The transcription factor nuclear κB (NF-<i>κ</i>B) regulates the expression multiple neuroinflammatory cytokines and chemokines activated that are damaging to neurons. Thus, inhibition NF-<i>κ</i>B signaling could be a promising therapeutic strategy for prevention injury. Nuclear orphan receptors NR4A family, including NR4A1 (Nur77) NR4A2 (Nurr1), can inhibit inflammatory effects NF-<i>κ</i>B, but no approved drugs target these receptors. Therefore, we postulated recently developed receptor ligand, 1,1bis (3′indolyl) 1(pmethoxyphenyl) methane (C-DIM5), would suppress NF-<i>κ</i>B-dependent gene astrocytes after treatment with 1-methyl-4-phenyl 1, 2, 3, 6-tetrahydropyridine (MPTP) interferon γ tumor necrosis <i>α</i>. C-DIM5 increased Nur77 mRNA suppressed genes. also inhibited NF<i>κ</i>B-regulated apoptotic genes quantitative polymerase chain reaction array studies effected p65 binding unique chromatin immunoprecipitation next-generation sequencing experiments did not prevent translocation nucleus, suggesting nuclear-specific mechanism. prevented export induced by MPTP simultaneously recruited Nurr1 consistent known transrepressive properties this receptor. Combined RNAi knockdown anti-inflammatory activity C-DIM5, demonstrating requires NF-<i>κ</i>B. Collectively, data demonstrate NR4A1/Nur77 NR4A2/Nurr1 dynamically regulated glia modulating transcriptional