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Previous research suggested that Nur77\u2019s 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.<\/jats:p>","DOI":"10.1093\/nar\/gkag808","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T11:42:36Z","timestamp":1785843756000},"source":"Crossref","is-referenced-by-count":0,"title":["Nuclear receptor Nur77 resolves the inflammatory response of macrophages primarily by regulating expression of AP-1 transcription factors and their target genes"],"prefix":"10.1093","volume":"54","author":[{"given":"Sanne C","family":"Lith","sequence":"first","affiliation":[{"name":"Amsterdam UMC location, location Academic Medical Center, Department of Medical Biochemistry, University of Amsterdam , 1105AZ Amsterdam ,","place":["The Netherlands"]},{"name":"Amsterdam Cardiovascular Sciences, University of Amsterdam , 1105AZ Amsterdam ,","place":["The Netherlands"]},{"name":"Amsterdam Institute for 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Institute for Immunology and Infectious Diseases, University of Amsterdam , 1105AZ Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6251-8161","authenticated-orcid":false,"given":"Ingeborg","family":"van\u00a0der\u00a0Made","sequence":"additional","affiliation":[{"name":"Amsterdam UMC location, location Academic Medical Center, Department of Medical Biochemistry, University of Amsterdam , 1105AZ Amsterdam ,","place":["The Netherlands"]},{"name":"Amsterdam Cardiovascular Sciences, University of Amsterdam , 1105AZ Amsterdam ,","place":["The Netherlands"]},{"name":"Amsterdam Institute for Immunology and Infectious Diseases, University of Amsterdam , 1105AZ Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz M","family":"Freire","sequence":"additional","affiliation":[{"name":"Amsterdam UMC location, location Academic Medical Center, Department 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Department of Medical Biochemistry, University of Amsterdam , 1105AZ Amsterdam ,","place":["The Netherlands"]},{"name":"Amsterdam Cardiovascular Sciences, University of Amsterdam , 1105AZ Amsterdam ,","place":["The Netherlands"]},{"name":"Amsterdam Institute for Immunology and Infectious Diseases, University of Amsterdam , 1105AZ Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9823-7289","authenticated-orcid":false,"given":"Wilbert","family":"Zwart","sequence":"additional","affiliation":[{"name":"Division of Oncogenomics, Netherlands Cancer Institute and Oncode Institute , 1066CX Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5981-121X","authenticated-orcid":false,"given":"Marten A","family":"Hoeksema","sequence":"additional","affiliation":[{"name":"Amsterdam UMC location, location Academic Medical Center, 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