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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 nuclear factor kappa B (NF-?B) 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 N?-hydroxy-nor-L-arginine, while ?-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.

SUBMITTER: Hannemann N

PROVIDER: S-EPMC6597220 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Hannemann Nicole N Cao Shan S Eriksson Daniel D Schnelzer Anne A Schnelzer Anne A Jordan Jutta J Eberhardt Martin M Schleicher Ulrike U Rech Jürgen J Ramming Andreas A Uebe Steffen S Ekici Arif A Cañete Juan D JD Chen Xiaoxiang X Bäuerle Tobias T Vera Julio J Bogdan Christian C Schett Georg G Bozec Aline A

The Journal of clinical investigation 20190416 7

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 re ...[more]

PMID: 30990796

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

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

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