Transcription factor Fra-1 targets arginase-1 to enhance macrophage-mediated inflammation in arthritis
Nicole Hannemann, … , Georg Schett, Aline Bozec
Nicole Hannemann, … , Georg Schett, Aline Bozec
Published July 1, 2019; First published April 16, 2019
Citation Information: J Clin Invest. 2019;129(7):2669-2684. https://doi.org/10.1172/JCI96832.
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Categories: Research Article Cell biology Inflammation

Transcription factor Fra-1 targets arginase-1 to enhance macrophage-mediated inflammation in arthritis

Abstract

The polarization of macrophages is regulated by transcription factors, such as NF-κB and activator protein 1 (AP-1). In this manuscript, we delineated the role of the transcription factor Fos-related antigen 1 (Fra-1) during macrophage activation and development of arthritis. Network level interaction analysis of microarray data derived from Fra-1– or Fra-2–deficient macrophages revealed a central role of Fra-1, but not of Fra-2, in orchestrating the expression of genes related to wound response, Toll-like receptor activation, and interleukin signaling. ChIP sequencing and standard ChIP analyses of macrophages identified arginase 1 (Arg1) as a target of Fra-1. Luciferase reporter assays revealed that Fra-1 downregulated Arg1 expression by direct binding to the promoter region. Using macrophage-specific Fra-1– or Fra-2–deficient mice, we observed enhanced expression and activity of Arg1 and a reduction of arthritis in the absence of Fra-1, but not of Fra-2. This phenotype was reversed by treatment with the arginase inhibitor Nω-hydroxy-nor-ʟ-arginine, while ʟ-arginine supplementation increased arginase activity and alleviated arthritis, supporting the notion that reduced arthritis in macrophage-specific Fra-1–deficient mice resulted from enhanced Arg1 expression and activity. Moreover, patients with active rheumatoid arthritis (RA) showed increased Fra-1 expression in the peripheral blood and elevated Fra-1 protein in synovial macrophages compared with RA patients in remission. In addition, the Fra-1/ARG1 ratio in synovial macrophages was related to RA disease activity. In conclusion, these data suggest that Fra-1 orchestrates the inflammatory state of macrophages by inhibition of Arg1 expression and thereby impedes the resolution of inflammation.

Authors

Nicole Hannemann, Shan Cao, Daniel Eriksson, Anne Schnelzer, Jutta Jordan, Martin Eberhardt, Ulrike Schleicher, Jürgen Rech, Andreas Ramming, Steffen Uebe, Arif Ekici, Juan D. Cañete, Xiaoxiang Chen, Tobias Bäuerle, Julio Vera, Christian Bogdan, Georg Schett, Aline Bozec

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Figure 10

Fra-1 and Arg1 expression in the joints of RA patients.

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Fra-1 and Arg1 expression in the joints of RA patients. (A) Fra-1 mRNA e...
(A) Fra-1 mRNA expression in peripheral blood cells of patients with RA at different levels of inflammatory disease activity measured by DAS28. DAS28 of less than 2.6 indicated low/no disease activity (n = 11), more than 2.7 and less than 5.1 indicated moderate disease activity (n = 11), and more than 5.2 indicated high disease activity (n = 12). (B) Correlation between mRNA expression of Fra-1 and Arg1 (left) or arginase activity (right) in peripheral blood cells or serum, respectively. Rel exp, relative expression. (C) Immunofluorescence image for CD68 (magenta), Fra-1 (green), Arg1 (red), and DAPI (blue) in joint sections from RA patients in remission (DAS28 = 1.81) and moderate/high disease activity (DAS28 = 4.01). Scale bars: 100 μm. Arrowheads point to CD68+ macrophages. White inset boxes are 3 times magnified from the original magnification. (D) CD68+ cells were quantified for their Fra-1/Arg1 ratio by the mean gray value in the synovial tissue of RA patients (n = 14) in remission (DAS28 < 2.6, n = 9) or moderate/high disease activity (DAS28>3.2, n = 5). Each point represents the ratio of the mean gray value (Fra-1/Arg1) per macrophage. (E) Schematic of Fra-1 actions in macrophages: Fra-1 blocks antiinflammatory responses in macrophages by the inhibition of the Arg1 pathways. *P < 0.05; **P < 0.01.