Mesenchymal stem cells (MSC) are highly immunosuppressive cells able to reduce chronic inflammation through the active release of mediators. Recently, we showed that glucocorticoid-induced leucine zipper (Gilz) expression by MSC is involved in their therapeutic effect by promoting the generation of regulatory T cells. However, the mechanisms underlying this pivotal role of Gilz remain elusive. Methods and Results In this study, we have uncovered evidence that Gilz modulates the phenotype and function of Th1 and Th17 cells likely by upregulating the level of Activin A and NO2 secreted by MSC. Adoptive transfer experiments sustained this Gilz-dependent suppressive effect of MSC on Th1 and Th17 cell functions. In immunoregulatory MSC, obtained by priming with IFN-γ and TNF-α, Gilz was translocated to the nucleus and bound to the promoters of inos and Activin βA to induce their expression. The increased expression of Activin A directly impacted on Th17 cells fate by repressing their differentiation program through the activation of Smad3/2 and enhancing IL-10 production. Conclusion Our results reveal how Gilz controls inos and Activin βA gene expression to ultimately assign immunoregulatory status to MSC able to repress the pathogenic Th17 cell differentiation program and uncover Activin A as a novel mediator of MSC in this process.
Bibliographical noteFunding Information:
This work was supported by Inserm, the University of Montpellier I and grants from the Medical Research Foundation (projet FRM 2011 "Comité Languedoc-Roussillon-Rouergue"), the French National Research Agency as part of the "Investments for the Future", ECellFrance consortium, program n° ANR-11-INBS-0005, the Société Française de Rhumatologie (SFR) and funding from the European Community's seventh framework program for the collaborative project: "REGENER-AR: Bringing Regenerative Medicine into the market: Allogeneic eASCs Phase IB/IIA clinical trial for treating Rheumatoid Arthritis" (contract no. 279174 EC). EFM and DN were supported by a grant from the National Health and Medical Research Council of Australia. D.A.M was supported by Fondecyt postdoctorado grant n° 3160525 and PLC by CONICYT through the program becas Chile folio n° 74140021.
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- Activin A
- Mesenchymal Stem Cells
- Th17 cells