Format

Send to

Choose Destination
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.

Author information

1
Department of Internal Medicine 3-Rheumatology and Immunology.
2
Institute of Radiology, Preclinical Imaging Platform Erlangen (PIPE).
3
Laboratory of Systems Tumor Immunology, Department of Dermatology.
4
Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, and.
5
Institute of Human Genetics, FAU and Universitätsklinikum Erlangen, Erlangen, Germany.
6
Departamento de Reumatología, Hospital Clínic de Barcelona e IDIBAPS, Barcelona, Spain.
7
Department of Rheumatology, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

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.

KEYWORDS:

Arthritis; Cell Biology; Inflammation; Macrophages

Comment in

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation Icon for PubMed Central
Loading ...
Support Center