We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Transcription factor Fra-1 targets arginase-1 to enhance macrophage-mediated inflammation in arthritis.
- Authors
Hannemann, Nicole; Shan Cao; Eriksson, Daniel; Schnelzer, Anne; Jordan, Jutta; Eberhardt, Martin; Schleicher, Ulrike; Rech, Jürgen; Ramming, Andreas; Uebe, Steffen; Ekici, Arif; Cañete, Juan D.; Xiaoxiang Chen; Bäuerle, Tobias; Vera, Julio; Bogdan, Christian; Schett, Georg; Bozec, Aline; Cao, Shan; Chen, Xiaoxiang
- Abstract
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.
- Subjects
TRANSCRIPTION factors; ARGININE; ARTHRITIS; GOLIMUMAB; AP-1 transcription factor; RHEUMATOID arthritis; TOLL-like receptors
- Publication
Journal of Clinical Investigation, 2019, Vol 129, Issue 7, p2669
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI96832