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    FADD, inflammation and rheumatoid arthritis

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    Principal investigator: Léa Rémy-Tourneur

    Contact : lea.remy-tourneur@parisdescartes.fr –Phone : +33 1 40 51 66 06

     

    Objective

    Besides being an essential adaptor for death receptors implicated in apoptosis, FADD (Fas-Associated Death Domain) is also involved in numerous physio-pathological processes including innate immunity, autophagy, cancer and inflammation. Thus, changes in FADD expression mostly have dramatic cellular consequences. Remarkably, we have previously described a new mechanism of FADD protein expression regulation by secretion and our recent works showed that FADD secretion is under the control of the NALP3 inflammasome, a multiprotein complex leading to cellular inflammatory responses. Moreover, we detected high level of soluble FADD in the sera of rheumatoid arthritis (RA) suffering patients but not in the sera from patients suffering from other rheumatisms and from healthy donor (collaboration with Dr Chiocchia, INSERM-UVSQ), making soluble FADD a new potential marker / actor of inflammation in RA. The global aim of this project is 1) to decipher the exact mechanisms leading to FADD secretion in human cells, 2) to identify the FADD secreting cells in RA, and 3) to evaluate the impact of such FADD secretion in inflammation development. Additionally to their fundamental interest, results of this study could have a strong impact in the understanding of the joint inflammation and open a new field of therapeutic investigations.

     

    The group

    Sara Mouasni, PhD scholarship starting September 1st 2015.

    Virginie Gonzalez, Research Technician

     

    Research interests

    Discovery of a FADD protein secretion process that is correlated to the development and aggressiveness of cancer cells opens a new field of investigation. Moreover, we have shown that soluble FADD appeared as an inflammatory marker in rheumatoid arthritis (RA) and thus could contribute to RA pathogenesis. As a consequence, a main part of the project will consist in deciphering the signalling pathway implicated in the FADD secretion process that occurs both spontaneously and in response to the NALP3 inflammasome activation. For this purpose, we developed an in vitro culture cell line model of FADD secretion using the THP-1 human monocytic cell lines which is classically used for inflammasome studies. Using CRISPR/Cas9 technology, we are generating key NALP3 inflammasome molecules-deficient THP-1 cells. In addition, we test the ability of monocytes derived from peripheral blood mononuclear cells (PBMC), cells from synovial fluid, and cultured synoviocytes from RA patients, to secrete FADD. Another part of the project will be to characterize the functional consequences of such a secretion for both secretory and surrounding cells. Finally, we want to identify the proteins co-secreted with FADD as they could constitute new therapeutic targets, in particular in RA.

     

    Main publications and patents

    Mouasni S, Tourneur L. 2018. FADD at the Crossroads between Cancer and Inflammation. Trends Immunol. 2018 Nov 3.

    Vilmont V., O. Filhol, A-M. Hesse, Y. Couté, C. Hue, L. Rémy-Tourneur, S. Mistou, C. Cochet and G. Chiocchia. 2015. Modulatory role of the anti-apoptotic protein kinase CK2 in the sub-cellular localization of Fas associated death domain protein (FADD). Biochim Biophys Acta. 1853(11 Pt A): 2885-96.

    Cimino Y., A. Costes, D. Damotte, P. Validire, S. Mistou, N. Cagnard, M. Alifano, JF. Régnard, G. Chiocchia, C. Sautès-Fridman, and L. Tourneur. 2012. FADD protein release mirrors the development and aggressiveness of human non-small cell lung cancer. British Journal of Cancer. 106(12):1989-96.

    Vilmont V., L. Tourneur, G. Chiocchia. 2012. Fas-associated death domain protein and adenosine partnership: fad in RA. Rheumatology (Oxford). 51(6):964-75.

    Tourneur L. and G. Chiocchia. 2010. FADD: a regulator of life and death. Trends in Immunology. 31(7): 260-69.

    Tourneur L., S. Mistou, A. Schmitt, G. Chiocchia. 2008. Adenosine receptors control a new pathway of FADD protein expression regulation by secretion. J Biol Chem. 283(26): 17929-17938.

    Tourneur L., S. Delluc, V. Levy, F. Valensi, I. Radford-Weiss, O. Legrand, J. Vargaftig, C. Boix, E. A. Macintyre, B. Varet, G. Chiocchia, A. Buzyn. 2004. Absence or low expression of Fas-Associated protein with Death Domain in acute myeloid leukemia cells predicts resistance to chemotherapy and poor outcome. Cancer Research. 64: 8101-8108.

     

    Financial supports

    These programs are supported by FONDATION ARTHRITIS.

     

     

     

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