The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells

Esperanza Perucha; Rossella Melchiotti; Jack A. Bibby; Wing Wu; Klaus Stensgaard Frederiksen; Ceri A. Roberts; Zoe Hall; Gaelle LeFriec; Kevin A. Robertson; Paul Lavender; Jens Gammeltoft Gerwien; Leonie S. Taams; Julian L. Griffin; Emanuele de Rinaldis; Lisa G.M. van Baarsen; Claudia Kemper; Peter Ghazal; Andrew P. Cope

doi:10.1038/s41467-019-08332-9

The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells

Esperanza Perucha^*, Rossella Melchiotti, Jack A. Bibby, Wing Wu, Klaus Stensgaard Frederiksen, Ceri A. Roberts, Zoe Hall, Gaelle LeFriec, Kevin A. Robertson, Paul Lavender, Jens Gammeltoft Gerwien, Leonie S. Taams, Julian L. Griffin, Emanuele de Rinaldis, Lisa G.M. van Baarsen, Claudia Kemper, Peter Ghazal, Andrew P. Cope

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Systemische Entzündungsforschung

3 Zitate (Scopus)

Abstract

The mechanisms controlling CD4 ⁺ T cell switching from an effector to an anti-inflammatory (IL-10 ⁺ ) phenotype play an important role in the persistence of chronic inflammatory diseases. Here, we identify the cholesterol biosynthesis pathway as a key regulator of this process. Pathway analysis of cultured cytokine-producing human T cells reveals a significant association between IL-10 and cholesterol metabolism gene expression. Inhibition of the cholesterol biosynthesis pathway with atorvastatin or 25-hydroxycholesterol during switching from IFNγ ⁺ to IL-10 ⁺ shows a specific block in immune resolution, defined as a significant decrease in IL-10 expression. Mechanistically, the master transcriptional regulator of IL10 in T cells, c-Maf, is significantly decreased by physiological levels of 25-hydroxycholesterol. Strikingly, progression to rheumatoid arthritis is associated with altered expression of cholesterol biosynthesis genes in synovial biopsies of predisposed individuals. Our data reveal a link between sterol metabolism and the regulation of the anti-inflammatory response in human CD4 ⁺ T cells.

Originalsprache	Englisch
Aufsatznummer	498
Zeitschrift	Nature Communications
Jahrgang	10
Ausgabenummer	1
Seiten (von - bis)	498
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-019-08332-9
Publikationsstatus	Veröffentlicht - 30.01.2019

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Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)

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Perucha, E., Melchiotti, R., Bibby, J. A., Wu, W., Frederiksen, K. S., Roberts, C. A., Hall, Z., LeFriec, G., Robertson, K. A., Lavender, P., Gerwien, J. G., Taams, L. S., Griffin, J. L., de Rinaldis, E., van Baarsen, L. G. M., Kemper, C., Ghazal, P., & Cope, A. P. (2019). The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells. Nature Communications, 10(1), 498. Artikel 498. https://doi.org/10.1038/s41467-019-08332-9

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title = "The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells",

abstract = " The mechanisms controlling CD4 + T cell switching from an effector to an anti-inflammatory (IL-10 + ) phenotype play an important role in the persistence of chronic inflammatory diseases. Here, we identify the cholesterol biosynthesis pathway as a key regulator of this process. Pathway analysis of cultured cytokine-producing human T cells reveals a significant association between IL-10 and cholesterol metabolism gene expression. Inhibition of the cholesterol biosynthesis pathway with atorvastatin or 25-hydroxycholesterol during switching from IFNγ + to IL-10 + shows a specific block in immune resolution, defined as a significant decrease in IL-10 expression. Mechanistically, the master transcriptional regulator of IL10 in T cells, c-Maf, is significantly decreased by physiological levels of 25-hydroxycholesterol. Strikingly, progression to rheumatoid arthritis is associated with altered expression of cholesterol biosynthesis genes in synovial biopsies of predisposed individuals. Our data reveal a link between sterol metabolism and the regulation of the anti-inflammatory response in human CD4 + T cells. ",

author = "Esperanza Perucha and Rossella Melchiotti and Bibby, {Jack A.} and Wing Wu and Frederiksen, {Klaus Stensgaard} and Roberts, {Ceri A.} and Zoe Hall and Gaelle LeFriec and Robertson, {Kevin A.} and Paul Lavender and Gerwien, {Jens Gammeltoft} and Taams, {Leonie S.} and Griffin, {Julian L.} and {de Rinaldis}, Emanuele and {van Baarsen}, {Lisa G.M.} and Claudia Kemper and Peter Ghazal and Cope, {Andrew P.}",

year = "2019",

month = jan,

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doi = "10.1038/s41467-019-08332-9",

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Perucha, E, Melchiotti, R, Bibby, JA, Wu, W, Frederiksen, KS, Roberts, CA, Hall, Z, LeFriec, G, Robertson, KA, Lavender, P, Gerwien, JG, Taams, LS, Griffin, JL, de Rinaldis, E, van Baarsen, LGM, Kemper, C, Ghazal, P & Cope, AP 2019, 'The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells', Nature Communications, Jg. 10, Nr. 1, 498, S. 498. https://doi.org/10.1038/s41467-019-08332-9

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T1 - The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells

AU - Perucha, Esperanza

AU - Melchiotti, Rossella

AU - Bibby, Jack A.

AU - Wu, Wing

AU - Frederiksen, Klaus Stensgaard

AU - Roberts, Ceri A.

AU - Hall, Zoe

AU - LeFriec, Gaelle

AU - Robertson, Kevin A.

AU - Lavender, Paul

AU - Gerwien, Jens Gammeltoft

AU - Taams, Leonie S.

AU - Griffin, Julian L.

AU - de Rinaldis, Emanuele

AU - van Baarsen, Lisa G.M.

AU - Kemper, Claudia

AU - Ghazal, Peter

AU - Cope, Andrew P.

PY - 2019/1/30

Y1 - 2019/1/30

N2 - The mechanisms controlling CD4 + T cell switching from an effector to an anti-inflammatory (IL-10 + ) phenotype play an important role in the persistence of chronic inflammatory diseases. Here, we identify the cholesterol biosynthesis pathway as a key regulator of this process. Pathway analysis of cultured cytokine-producing human T cells reveals a significant association between IL-10 and cholesterol metabolism gene expression. Inhibition of the cholesterol biosynthesis pathway with atorvastatin or 25-hydroxycholesterol during switching from IFNγ + to IL-10 + shows a specific block in immune resolution, defined as a significant decrease in IL-10 expression. Mechanistically, the master transcriptional regulator of IL10 in T cells, c-Maf, is significantly decreased by physiological levels of 25-hydroxycholesterol. Strikingly, progression to rheumatoid arthritis is associated with altered expression of cholesterol biosynthesis genes in synovial biopsies of predisposed individuals. Our data reveal a link between sterol metabolism and the regulation of the anti-inflammatory response in human CD4 + T cells.

AB - The mechanisms controlling CD4 + T cell switching from an effector to an anti-inflammatory (IL-10 + ) phenotype play an important role in the persistence of chronic inflammatory diseases. Here, we identify the cholesterol biosynthesis pathway as a key regulator of this process. Pathway analysis of cultured cytokine-producing human T cells reveals a significant association between IL-10 and cholesterol metabolism gene expression. Inhibition of the cholesterol biosynthesis pathway with atorvastatin or 25-hydroxycholesterol during switching from IFNγ + to IL-10 + shows a specific block in immune resolution, defined as a significant decrease in IL-10 expression. Mechanistically, the master transcriptional regulator of IL10 in T cells, c-Maf, is significantly decreased by physiological levels of 25-hydroxycholesterol. Strikingly, progression to rheumatoid arthritis is associated with altered expression of cholesterol biosynthesis genes in synovial biopsies of predisposed individuals. Our data reveal a link between sterol metabolism and the regulation of the anti-inflammatory response in human CD4 + T cells.

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The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells

Abstract

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