IL-1β induced HIF-1α inhibits the differentiation of human FOXP3+ T cells

Abstract Differentiation of regulatory Treg (Treg) in the periphery is critical to control inflammatory processes. Although polarization of inducible Treg (iTreg) often occurs in an inflammatory environment, the effects exerted by inflammation on human iTreg differentiation have not been extensively...

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Autores principales:	Lea M. Feldhoff, Cesar M. Rueda, Maria E. Moreno-Fernandez, Johanna Sauer, Courtney M. Jackson, Claire A. Chougnet, Jan Rupp
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ebb9d13629594450a5de8b26a4278e2c
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spelling	oai:doaj.org-article:ebb9d13629594450a5de8b26a4278e2c2021-12-02T15:05:31ZIL-1β induced HIF-1α inhibits the differentiation of human FOXP3+ T cells10.1038/s41598-017-00508-x2045-2322https://doaj.org/article/ebb9d13629594450a5de8b26a4278e2c2017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00508-xhttps://doaj.org/toc/2045-2322Abstract Differentiation of regulatory Treg (Treg) in the periphery is critical to control inflammatory processes. Although polarization of inducible Treg (iTreg) often occurs in an inflammatory environment, the effects exerted by inflammation on human iTreg differentiation have not been extensively studied. We observed that IL-1β significantly reduced the frequency of FOXP3+ T cells under iTreg-polarizing conditions. Mechanistically, we show that IL-1β activated mTORC1 and downstream upregulated hypoxia inducible factor-1 (HIF-1α) expression. Using specific inhibitors, we demonstrated that both steps were critical in the deleterious effect of IL-1β on Treg differentiation. Chemical stabilization of HIF-1α by Dimethyloxalylglycine (DMOG) also significantly impaired iTreg differentiation. Interestingly, while IL-1β-treated cells exhibited only minor changes in metabolism, DMOG treatment decreased iTreg mitochondrial respiration and increased their glycolytic capacity. In conclusion, exposure to inflammatory stimuli profoundly inhibits human Treg differentiation HIF-1α dependent, suggesting that targeting HIF-1α could be a strategy to foster iTreg differentiation in an inflammatory milieu. However, IL-1β deleterious effect does not appear to be completely driven by metabolic changes. These data thus suggest that several mechanisms contribute to the regulation of iTreg differentiation, but the timing and respective requirement for each pathway vary depending on the milieu in which iTreg differentiate.Lea M. FeldhoffCesar M. RuedaMaria E. Moreno-FernandezJohanna SauerCourtney M. JacksonClaire A. ChougnetJan RuppNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lea M. Feldhoff Cesar M. Rueda Maria E. Moreno-Fernandez Johanna Sauer Courtney M. Jackson Claire A. Chougnet Jan Rupp IL-1β induced HIF-1α inhibits the differentiation of human FOXP3+ T cells
description	Abstract Differentiation of regulatory Treg (Treg) in the periphery is critical to control inflammatory processes. Although polarization of inducible Treg (iTreg) often occurs in an inflammatory environment, the effects exerted by inflammation on human iTreg differentiation have not been extensively studied. We observed that IL-1β significantly reduced the frequency of FOXP3+ T cells under iTreg-polarizing conditions. Mechanistically, we show that IL-1β activated mTORC1 and downstream upregulated hypoxia inducible factor-1 (HIF-1α) expression. Using specific inhibitors, we demonstrated that both steps were critical in the deleterious effect of IL-1β on Treg differentiation. Chemical stabilization of HIF-1α by Dimethyloxalylglycine (DMOG) also significantly impaired iTreg differentiation. Interestingly, while IL-1β-treated cells exhibited only minor changes in metabolism, DMOG treatment decreased iTreg mitochondrial respiration and increased their glycolytic capacity. In conclusion, exposure to inflammatory stimuli profoundly inhibits human Treg differentiation HIF-1α dependent, suggesting that targeting HIF-1α could be a strategy to foster iTreg differentiation in an inflammatory milieu. However, IL-1β deleterious effect does not appear to be completely driven by metabolic changes. These data thus suggest that several mechanisms contribute to the regulation of iTreg differentiation, but the timing and respective requirement for each pathway vary depending on the milieu in which iTreg differentiate.
format	article
author	Lea M. Feldhoff Cesar M. Rueda Maria E. Moreno-Fernandez Johanna Sauer Courtney M. Jackson Claire A. Chougnet Jan Rupp
author_facet	Lea M. Feldhoff Cesar M. Rueda Maria E. Moreno-Fernandez Johanna Sauer Courtney M. Jackson Claire A. Chougnet Jan Rupp
author_sort	Lea M. Feldhoff
title	IL-1β induced HIF-1α inhibits the differentiation of human FOXP3+ T cells
title_short	IL-1β induced HIF-1α inhibits the differentiation of human FOXP3+ T cells
title_full	IL-1β induced HIF-1α inhibits the differentiation of human FOXP3+ T cells
title_fullStr	IL-1β induced HIF-1α inhibits the differentiation of human FOXP3+ T cells
title_full_unstemmed	IL-1β induced HIF-1α inhibits the differentiation of human FOXP3+ T cells
title_sort	il-1β induced hif-1α inhibits the differentiation of human foxp3+ t cells
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ebb9d13629594450a5de8b26a4278e2c
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IL-1β induced HIF-1α inhibits the differentiation of human FOXP3+ T cells

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