Authors
Sanne C Lith, Sebastian Gregoricchio, Claudia M van Tiel, Ingeborg van der Made, Beatriz M Freire, Simon Linder, Sanne Jacobs, Onno Bleijerveld, Liesbeth Hoekman, Guglielmo L Alonzo, Wilbert Zwart, Marten A Hoeksema, Carlie J M de Vries
Published in
Nucleic acids research. Volume 54. Issue 15. Aug 10, 2026.
Abstract
The nuclear receptor Nur77 plays a crucial, protective role in chronic inflammatory diseases and deficiency of Nur77 in macrophages results in excessive pro-inflammatory cytokine secretion. Previous research suggested that Nur77's regulatory function in inflammation is due to repression of the pro-inflammatory transcription factor NF-kB, but the underlying mechanism remains unclear. To address this, we applied a genome-wide, multi-omics approach in LPS-stimulated RAW264.7 macrophages with inducible Nur77 expression. Key findings were validated in wild-type and Nur77-deficient bone marrow-derived macrophages. We show that Nur77 suppresses the expression of inflammatory genes through a dual mechanism wherein Nur77 acts as a repressor of AP-1 targets at two levels: first, Nur77 occupies regulatory elements proximal to AP-1 target genes through AP-1 motifs and second, Nur77 regulates the expression of AP-1 family members themselves. These repressive activities of Nur77 result in diminished RNA Pol II on AP-1 genes and their targets. The first zinc finger of the Nur77 DNA-binding domain is required to reduce AP-1 activity. In summary, Nur77 represses macrophage inflammation through regulation of both immediate-early AP-1 expression, as well as inhibition of AP-1-driven gene programs.
PMID:
42605805
Bibliographic data and abstract were imported from PubMed on 17 Aug 2026.
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