title: The nuclear receptor Nr4a1 mediates anti-inflammatory effects of apoptotic cells.
abstract: Uptake of apoptotic cells (ACs) by macrophages ensures the nonimmunogenic clearance of dying cells, as well as the maintenance of self-tolerance to AC-derived autoantigens. Upon ingestion, ACs exert an inhibitory influence on the inflammatory signaling within the phagocyte. However, the molecular signals that mediate these immune-modulatory properties of ACs are incompletely understood. In this article, we show that the phagocytosis of apoptotic thymocytes was enhanced in tissue-resident macrophages where this process resulted in the inhibition of NF-κB signaling and repression of inflammatory cytokines, such as IL-12. In parallel, ACs induced a robust expression of a panel of immediate early genes, which included the Nr4a subfamily of nuclear receptors. Notably, deletion of Nr4a1 interfered with the anti-inflammatory effects of ACs in macrophages and restored both NF-κB signaling and IL-12 expression. Accordingly, Nr4a1 mediated the anti-inflammatory properties of ACs in vivo and was required for maintenance of self-tolerance in the murine model of pristane-induced lupus. Thus, our data point toward a key role for Nr4a1 as regulator of the immune response to ACs and of the maintenance of tolerance to "dying self."
authors.affiliation: Department of Internal Medicine 3 and Institute for Clinical Immunology, Erlangen, Erlangen 91054, Germany;
authors.forename: Natacha
authors.initials: N
authors.lastname: Ipseiz
authors.forename: Stefan
authors.initials: S
authors.lastname: Uderhardt
authors.forename: Carina
authors.initials: C
authors.lastname: Scholtysek
authors.forename: Martin
authors.initials: M
authors.lastname: Steffen
authors.forename: Gernot
authors.initials: G
authors.lastname: Schabbauer
authors.forename: Aline
authors.initials: A
authors.lastname: Bozec
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Gerhard
authors.initials: G
authors.lastname: Krönke
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000502:physiology*; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D016328:NF-kappa B; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018664:Interleukin-12