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01.12 Fra-1 transcription factor expression in macrophages foster inflammation during rheumatoid arthritis development
  1. Nicole Hannemann1,
  2. Anne Schnelzer1,
  3. Jutta Jordan2,
  4. Martin Eberhardt3,
  5. Ulrike Schleicher4,
  6. Axel Hueber1,
  7. Stephen Reid5,
  8. Sophia Sonnewald5,
  9. Tobias Bäuerle2,
  10. Julio Vera3,
  11. Christian Bogdan4,
  12. Georg Schett1,
  13. Aline Bozec1
  1. 1Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Internal Medicine 3 – Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen, Germany
  2. 2Institute of Radiology, Preclinical Imaging Platform Erlangen (PIPE) Universitätsklinikum Erlangen, Erlangen, Germany
  3. 3Department of Dermatology, Laboratory of Systems Tumour Immunology Universitätsklinikum Erlangen, Erlangen, Germany
  4. 4Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen, Erlangen Germany
  5. 5Division of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg (FAU),Erlangen, Germany

Abstract

Background The polarisation of macrophages leads to diverse populations, which are associated to a complex regulatory network of transcription factors. The activator protein (AP)−1 transcription factor family, specifically FOS proteins can regulate macrophage cytokines production. Because of the production of diverse pro-inflammatory and destructive molecules, macrophages are central players in chronic inflammation and bone destruction of rheumatoid arthritis (RA). Here, we delineate the diverse functions of Fra-1 and Fra-2 in the complex network of macrophage activations during RA development.

Material and methods To determine Fra-1 and Fra-2 roles during macrophage activation, Fra-1 or Fra-2 deficient peritoneal macrophages were used for microarray and quantitative real-time PCR analysis. In addition, promoter from genes found differentially expressed were analysed by chromatin immunoprecipitation (ChIP) analysis to discover directs targets of Fra-1 or Fra-2 in macrophages. To address the physiological roles of Fra-1 and Fra-2 in macrophages, the serum induced arthritis (K/BxN) model was applied to Fra-1ΔMx or Fra-2ΔLysM deficient mice.

Results Microarray analysis and subsequent gene ontology cluster enrichment highlight the specific role of Fra-1 during macrophages activation, whereas Fra-2 seems less essential for macrophage activated pathways. Additionally, the KEGG cluster analysis links Fra-1 expression to autoimmune diseases, such as RA. Applying the K/BxN serum transfer to Fra-2ΔLysM or Fra-1ΔMx mice, we could show that only Fra-1 deficient mice have a decreased arthritis severity, which was accompanied with a strong increased Arginase-1 (Arg1) expression in mice joints. Mechanistically, ChIP analysis confirmed that Fra-1 but not Fra-2 directly regulates Nos2 and Arg1 promoters in macrophages. Furthermore, the inhibition of Arg1 by Nω-hydroxy-nor-Arginine (NOHA) rescued the phenotype of Fra-1 mutant mice. Suggesting that Fra-1 promotes arthritic joint inflammation by inhibiting Arg1 expression, this probably leads to an increased resolution of inflammation in RA.

Conclusion We showed that Fra-1 defines the activation status of macrophages. Physiologically, Fra-1 regulates the Arg1/iNos axis thus promoting inflammation and bone destruction in RA. The role of Fra-1 in macrophages is unique, since Fra-2 cannot recapitulate Fra-1 functions. In conclusion, our data describe a new role of Fra-1 in macrophages activation in the maintenance of inflammation and joint destruction during acute RA.

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