Journal Article

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

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

2020

Overview

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. IL-10 production by B cells is integral to regulation and resolution of inflammation. Here the authors show that cholesterol metabolism can control B cell IL-10 production via a geranylgeranyl pyrophosphate-dependent mechanism.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/31 / 13/95 / 38 / 38/91 / 631/250/127/1213 / 631/250/1619/40 / 631/250/256 / 631/443/319/1642/2037 / 82/80 / AKT protein / Animals / Antigens, CD19 - metabolism / B-Lymphocytes, Regulatory - metabolism / Cholesterol / Cholesterol - metabolism / Class I Phosphatidylinositol 3-Kinases - metabolism / Coculture Techniques / Hereditary Autoinflammatory Diseases - metabolism / Humanities and Social Sciences / Humans / Inflammation / Integrals / Interleukin 10 / Interleukin-10 - metabolism / Kinases / Lipid metabolism / Lymphocytes B / Lymphocytes T / Macrophages - metabolism / Metabolic pathways / Metabolic Syndrome - metabolism / Metabolism / Mevalonate kinase / Mevalonate Kinase Deficiency - metabolism / Mevalonic acid / Mice / multidisciplinary / Mutation / Phosphatidylinositol 3-Kinases - metabolism / Polyisoprenyl Phosphates - metabolism / Positive Regulatory Domain I-Binding Factor 1 - metabolism / Priming / Principal Component Analysis / Science / Science (multidisciplinary) / Signal Transduction / Supplements / Th1 Cells - metabolism / Toll-Like Receptor 9 - metabolism / Tumor Necrosis Factor-alpha - metabolism