Gilz-activin a as a novel signaling axis orchestrating mesenchymal stem cell and Th17 cell interplay

Patricia Luz-Crawford, Gabriel Espinosa-Carrasco, Natacha Ipseiz, Rafael Contreras, Gautier Tejedor, Daniel A. Medina, Ana Maria Vega-Letter, Devi Ngo, Eric F. Morand, Jérôme Pène, Javier Hernandez, Christian Jorgensen, Farida Djouad

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)846-859
Number of pages14
JournalTheranostics
Volume8
Issue number3
DOIs
Publication statusPublished - 1 Jan 2018

Keywords

  • Activin A
  • Gilz
  • Immunosuppression
  • Mesenchymal Stem Cells
  • Th17 cells

Cite this

Luz-Crawford, P., Espinosa-Carrasco, G., Ipseiz, N., Contreras, R., Tejedor, G., Medina, D. A., ... Djouad, F. (2018). Gilz-activin a as a novel signaling axis orchestrating mesenchymal stem cell and Th17 cell interplay. Theranostics, 8(3), 846-859. https://doi.org/10.7150/THNO.21793
Luz-Crawford, Patricia ; Espinosa-Carrasco, Gabriel ; Ipseiz, Natacha ; Contreras, Rafael ; Tejedor, Gautier ; Medina, Daniel A. ; Vega-Letter, Ana Maria ; Ngo, Devi ; Morand, Eric F. ; Pène, Jérôme ; Hernandez, Javier ; Jorgensen, Christian ; Djouad, Farida. / Gilz-activin a as a novel signaling axis orchestrating mesenchymal stem cell and Th17 cell interplay. In: Theranostics. 2018 ; Vol. 8, No. 3. pp. 846-859.
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abstract = "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.",
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author = "Patricia Luz-Crawford and Gabriel Espinosa-Carrasco and Natacha Ipseiz and Rafael Contreras and Gautier Tejedor and Medina, {Daniel A.} and Vega-Letter, {Ana Maria} and Devi Ngo and Morand, {Eric F.} and J{\'e}r{\^o}me P{\`e}ne and Javier Hernandez and Christian Jorgensen and Farida Djouad",
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Luz-Crawford, P, Espinosa-Carrasco, G, Ipseiz, N, Contreras, R, Tejedor, G, Medina, DA, Vega-Letter, AM, Ngo, D, Morand, EF, Pène, J, Hernandez, J, Jorgensen, C & Djouad, F 2018, 'Gilz-activin a as a novel signaling axis orchestrating mesenchymal stem cell and Th17 cell interplay', Theranostics, vol. 8, no. 3, pp. 846-859. https://doi.org/10.7150/THNO.21793

Gilz-activin a as a novel signaling axis orchestrating mesenchymal stem cell and Th17 cell interplay. / Luz-Crawford, Patricia; Espinosa-Carrasco, Gabriel; Ipseiz, Natacha; Contreras, Rafael; Tejedor, Gautier; Medina, Daniel A.; Vega-Letter, Ana Maria; Ngo, Devi; Morand, Eric F.; Pène, Jérôme; Hernandez, Javier; Jorgensen, Christian; Djouad, Farida.

In: Theranostics, Vol. 8, No. 3, 01.01.2018, p. 846-859.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Gilz-activin a as a novel signaling axis orchestrating mesenchymal stem cell and Th17 cell interplay

AU - Luz-Crawford, Patricia

AU - Espinosa-Carrasco, Gabriel

AU - Ipseiz, Natacha

AU - Contreras, Rafael

AU - Tejedor, Gautier

AU - Medina, Daniel A.

AU - Vega-Letter, Ana Maria

AU - Ngo, Devi

AU - Morand, Eric F.

AU - Pène, Jérôme

AU - Hernandez, Javier

AU - Jorgensen, Christian

AU - Djouad, Farida

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Activin A

KW - Gilz

KW - Immunosuppression

KW - Mesenchymal Stem Cells

KW - Th17 cells

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Luz-Crawford P, Espinosa-Carrasco G, Ipseiz N, Contreras R, Tejedor G, Medina DA et al. Gilz-activin a as a novel signaling axis orchestrating mesenchymal stem cell and Th17 cell interplay. Theranostics. 2018 Jan 1;8(3):846-859. https://doi.org/10.7150/THNO.21793