Abstract
The therapeutic effect of mesenchymal stem cells (MSCs) in multiple sclerosis (MS) and the experimental autoimmune encephalomyelitis (EAE) model has been well described. This effect is, in part, mediated through the inhibition of IL17-producing cells and the generation of regulatory T cells. While proinflammatory cytokines such as IFNγ, TNFα, and IL1β have been shown to enhance MSCs immunosuppressive function, the role of IL17 remains poorly elucidated. The aim of this study was, therefore, to investigate the role of the IL17/IL17R pathway on MSCs immunoregulatory effects focusing on Th17 cell generation in vitro and on Th17-mediated EAE pathogenesis in vivo. In vitro, we showed that the immunosuppressive effect of MSCs on Th17 cell proliferation and differentiation is partially dependent on IL17RA expression. This was associated with a reduced expression level of MSCs immunosuppressive mediators such as VCAM1, ICAM1, and PD-L1 in IL17RA−/− MSCs as compared to wild-type (WT) MSCs. In the EAE model, we demonstrated that while WT MSCs significantly reduced the clinical scores of the disease, IL17RA−/− MSCs injected mice exhibited a clinical worsening of the disease. The disability of IL17RA−/− MSCs to reduce the progression of the disease paralleled the inability of these cells to reduce the frequency of Th17 cells in the draining lymph node of the mice as compared to WT MSCs. Moreover, we showed that the therapeutic effect of MSCs was correlated with the generation of classical Treg bearing the CD4+CD25+Foxp3+ signature in an IL17RA-dependent manner. Our findings reveal a novel role of IL17RA on MSCs immunosuppressive and therapeutic potential in EAE and suggest that the modulation of IL17RA in MSCs could represent a novel method to enhance their therapeutic effect in MS.
Highlights
The critical role of IL17 in the development of autoimmune and inflammatory disorders such as multiple sclerosis (MS) has been largely investigated [1,2,3,4]
To determine the role of the IL17/IL17R axis in mesenchymal stem cells (MSCs)-mediated immunomodulatory effect, we first evaluated if MSCs express the different subunits of the IL17R (A and C) that bind to the IL17A isoform
As compared to MSCs transfected with a control siRNA, MSCs silenced for IL17RA exhibited a significantly lower inhibitory effect on Th17 cells
Summary
The critical role of IL17 in the development of autoimmune and inflammatory disorders such as multiple sclerosis (MS) has been largely investigated [1,2,3,4]. IL17RA is ubiquitously expressed; the main responses to IL17A have been reported to occur in fibroblasts and endothelial cells [11,12,13]. In contrast to most interleukin receptors, the expression levels of IL17RA are functionally significant since high levels of IL17RA receptor are required for an effective response [16, 17]. Another particularity of IL17RA resides in its capacity to limit the signaling pathway via the internalization of its ligand. After IL17 binding, it is internalized and removed from the milieu in parallel with a decrease of IL17RA expression level at the cell surface [15]
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