Article Text

PDF
A6.17 Fra-1: Dr Jekyll or Mr Hyde for the resolution of inflammation in rheumatoid arthritis
  1. N Hannemann1,2,
  2. U Schleicher3,
  3. C Bogdan3,
  4. W Baum1,
  5. G Schett1,
  6. A Bozec1,2
  1. 1Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Nikolaus Fiebiger Center of Molecular Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
  3. 3Department of Microbiology, University of Erlangen-Nuremberg, Erlangen, Germany

Abstract

One feature of the AP-1 transcription factor family is their ability to regulate inflammatory processes and the activation and formation of osteoclasts. To test whether AP-1 expression is involved in rheumatoid arthritis (RA), serum K/BxN transfer model (SIA) is used. At the molecular levels, AP-1 expression analyses in wildtype joints show increased Fra-1, Fra-2 and cFos mRNA levels after SIA, whereas these Fos members are decreased in Fra-1fl/fl MxCre+mice after SIA, suggesting that Fra-2 and cFos expression are Fra-1 dependent. In addition, despite a similar rise of the disease in Fra-1deficient mice and wildtype littermates, Fra-1 deleted mice show a faster resolution of the disease than littermate controls, with lower inflammation area, bone erosion and osteoclast number. The pro- and anti-inflammatory cytokines profiling in the joints reveal a decreased TNF and increased IL-10 levels in Fra-1deletedmice compared to littermate controls. Moreover, knowing the essential actions of macrophages (Mφ) in joint destruction and remodelling, the expression of Mφ-specific molecules CD11c, CD206 and Arginase-1 (Arg-1) were analysed. Interestingly, CD206 and CD11c mRNA levels were decreased, whereas Arg-1 expression was highly increased in Fra-1fl/fl MxCre+joints compared to wildtype littermates, suggesting an alteration of Mφ polarisation in Fra-1 mutant mice. Indeed, in vitro stimulation of Fra-1 deleted Mφ with LPS and apoptotic cells, confirmed that (i) Fra-2 and cFos expression were Fra-1 dependent and that (ii) absence of Fra-1 altered Mφ polarisation, reaffirming the essential role of Fra-1 in pro-inflammatory Mφ activation. Finally, we found that Fra-1 can directly binds and regulates CD206, CD11c and Arg-1 promoters, and thereby regulates Mφ differentiation in RA. In conclusion, our data describe a new role of Fra-1 in Mφ activation in the maintenance of inflammation and joint destruction during acute RA.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.