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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginase / biosynthesis*
  • Arginase / genetics
  • Arthritis, Rheumatoid*
  • Fos-Related Antigen-2 / genetics
  • Fos-Related Antigen-2 / metabolism
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism*
  • Synovial Membrane / metabolism*
  • Synovial Membrane / pathology

Substances

  • FOSL2 protein, human
  • Fos-Related Antigen-2
  • Fosl2 protein, mouse
  • Proto-Oncogene Proteins c-fos
  • fos-related antigen 1
  • ARG1 protein, human
  • Arg1 protein, mouse
  • Arginase

Grant support

grant CRC1181 project A01 to A.B. and G.S., grant CRC1181 project C04 to C.B. and U.S., BO3811/1-6 to A.B., Emmy Noether grant BO3811/1-1 to A.B.