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The nuclear receptor Nr4a1 mediates anti-inflammatory effects of apoptotic cells

Ipseiz, Natacha, Uderhardt, Stefan, Scholtysek, Carina, Steffen, Martin, Schabbauer, Gernot, Bozec, Aline, Schett, Georg and Krönke, Gerhard 2014. The nuclear receptor Nr4a1 mediates anti-inflammatory effects of apoptotic cells. The Journal of Immunology 192 (10) , pp. 4852-4858. 10.4049/jimmunol.1303377

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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.”

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Association of Immunologists
ISSN: 0022-1767
Last Modified: 20 Dec 2019 11:31

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