Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate

Jack A. Bibby; Harriet A. Purvis; Thomas Hayday; Anita Chandra; Klaus Okkenhaug; Sofia Rosenzweig; Ivona Aksentijevich; Michael Wood; Helen J. Lachmann; Claudia Kemper; Andrew P. Cope; Esperanza Perucha

doi:10.1038/s41467-020-17179-4

Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate

Jack A. Bibby^*, Harriet A. Purvis, Thomas Hayday, Anita Chandra, Klaus Okkenhaug, Sofia Rosenzweig, Ivona Aksentijevich, Michael Wood, Helen J. Lachmann, Claudia Kemper, Andrew P. Cope, Esperanza Perucha

^*Corresponding author for this work

Institute of Systemic Inflamation Research

74 Citations (Scopus)

Abstract

Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) is required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications control signaling through PI3Kδ-AKT-GSK3, which in turn promote BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induce poor IL-10 responses and are functionally impaired. Moreover, metabolic supplementation with GGPP is able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.

Original language	English
Article number	3412
Journal	Nature Communications
Volume	11
Issue number	1
Pages (from-to)	3412
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-020-17179-4
Publication status	Published - 08.07.2020

Funding

We thank all the healthy donors and patients for their support. This research was funded/ supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London and/or the NIHR Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care This work was also supported by: the IMI-funded project BeTheCure (115142-2); EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking RTCure (777357) (both E.P. and A.P.C.); the National Institute for Health Research Biomedical Research Centre, at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London (J.A.B.); Intramural Research Programs of the National Human Genome Research Institute (I.A. and S.R.); MRC (MR/ M012328/2, K.O.); Wellcome Trust (206618/Z/17/Z, A.C.)

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-020-17179-4

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Bibby, J. A., Purvis, H. A., Hayday, T., Chandra, A., Okkenhaug, K., Rosenzweig, S., Aksentijevich, I., Wood, M., Lachmann, H. J., Kemper, C., Cope, A. P., & Perucha, E. (2020). Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate. Nature Communications, 11(1), 3412. Article 3412. https://doi.org/10.1038/s41467-020-17179-4

@article{444b52f364204ca3bc515abe9947beac,

title = "Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate",

abstract = "Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) is required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications control signaling through PI3Kδ-AKT-GSK3, which in turn promote BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induce poor IL-10 responses and are functionally impaired. Moreover, metabolic supplementation with GGPP is able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.",

author = "Bibby, \{Jack A.\} and Purvis, \{Harriet A.\} and Thomas Hayday and Anita Chandra and Klaus Okkenhaug and Sofia Rosenzweig and Ivona Aksentijevich and Michael Wood and Lachmann, \{Helen J.\} and Claudia Kemper and Cope, \{Andrew P.\} and Esperanza Perucha",

note = "Funding Information: We thank all the healthy donors and patients for their support. This research was funded/ supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy{\textquoteright}s and St. Thomas{\textquoteright} NHS Foundation Trust and King{\textquoteright}s College London and/or the NIHR Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care This work was also supported by: the IMI-funded project BeTheCure (115142-2); EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking RTCure (777357) (both E.P. and A.P.C.); the National Institute for Health Research Biomedical Research Centre, at Guy{\textquoteright}s and St. Thomas{\textquoteright} NHS Foundation Trust and King{\textquoteright}s College London (J.A.B.); Intramural Research Programs of the National Human Genome Research Institute (I.A. and S.R.); MRC (MR/ M012328/2, K.O.); Wellcome Trust (206618/Z/17/Z, A.C.) Publisher Copyright: {\textcopyright} 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

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doi = "10.1038/s41467-020-17179-4",

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T1 - Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate

AU - Bibby, Jack A.

AU - Purvis, Harriet A.

AU - Hayday, Thomas

AU - Chandra, Anita

AU - Okkenhaug, Klaus

AU - Rosenzweig, Sofia

AU - Aksentijevich, Ivona

AU - Wood, Michael

AU - Lachmann, Helen J.

AU - Kemper, Claudia

AU - Cope, Andrew P.

AU - Perucha, Esperanza

N1 - Funding Information: We thank all the healthy donors and patients for their support. This research was funded/ supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London and/or the NIHR Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care This work was also supported by: the IMI-funded project BeTheCure (115142-2); EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking RTCure (777357) (both E.P. and A.P.C.); the National Institute for Health Research Biomedical Research Centre, at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London (J.A.B.); Intramural Research Programs of the National Human Genome Research Institute (I.A. and S.R.); MRC (MR/ M012328/2, K.O.); Wellcome Trust (206618/Z/17/Z, A.C.) Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/7/8

Y1 - 2020/7/8

N2 - Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) is required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications control signaling through PI3Kδ-AKT-GSK3, which in turn promote BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induce poor IL-10 responses and are functionally impaired. Moreover, metabolic supplementation with GGPP is able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.

AB - Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) is required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications control signaling through PI3Kδ-AKT-GSK3, which in turn promote BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induce poor IL-10 responses and are functionally impaired. Moreover, metabolic supplementation with GGPP is able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.

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JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3412

ER -

Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate

Abstract

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