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J Clin Invest. 2019 Apr 16;129(7):2669-2684. doi: 10.1172/JCI96832.

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

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Department of Internal Medicine 3-Rheumatology and Immunology.
Institute of Radiology, Preclinical Imaging Platform Erlangen (PIPE).
Laboratory of Systems Tumor Immunology, Department of Dermatology.
Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, and.
Institute of Human Genetics, FAU and Universitätsklinikum Erlangen, Erlangen, Germany.
Departamento de Reumatología, Hospital Clínic de Barcelona e IDIBAPS, Barcelona, Spain.
Department of Rheumatology, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.


The polarization of macrophages is regulated by transcription factors such as nuclear factor kappa B (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. Chromatin-immunoprecipitation (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 down-regulated Arg1 expression by direct binding to the promoter region. Using macrophage-specific Fra-1- or Fra-2- deficient mice, we observed an 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-L-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 RA showed increased Fra-1 expression in the peripheral blood and elevated Fra-1 protein in synovial macrophages compared to 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.


Arthritis; Cell Biology; Inflammation; Macrophages

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