Sterol metabolism controls TH17 differentiation by generating endogenous RORγ agonists

Abstract

Retinoic acid receptor-related orphan receptor γ (RORγt) controls the differentiation of naive CD4(+) T cells into the TH17 lineage, which are critical cells in the pathogenesis of autoimmune diseases. Here we report that during TH17 differentiation, cholesterol biosynthesis and uptake programs are induced, whereas their metabolism and efflux programs are suppressed. These changes result in the accumulation of the cholesterol precursor, desmosterol, which functions as a potent endogenous RORγ agonist. Generation of cholesterol precursors is essential for TH17 differentiation as blocking cholesterol synthesis with chemical inhibitors at steps before the formation of active precursors reduces differentiation. Upon activation, metabolic changes also lead to production of specific sterol-sulfate conjugates that favor activation of RORγ over the TH17-inhibiting sterol receptor LXR. Thus, TH17 differentiation is orchestrated by coordinated sterol synthesis, mobilization and metabolism to selectively activate RORγ.

Immunologic impact of the intestine in metabolic disease

“…The LXR reduces Th17 lineage differentiation (46), as this effect competes with endogenous oxysterol ligands for RORγt (47) while gut-specific targeting of the FXR exerts antiinflammatory effects (48). A fat-enriched diet also reduces the number of ileal IL-17/RORγt CD4 + T cells, and IL-17/RORγt-deficient T cells are associated with the induction of glucose intolerance and obesity (49).…”

Transcriptional Regulation of Cytosolic Sulfotransferase 1C2 by Intermediates of the Cholesterol Biosynthetic Pathway in Primary Cultured Rat Hepatocytes

“…Additionally, LXR regulates the expression of SULT2A1 and 2B1b (Jiang et al, 2005;Ou et al, 2014), and several oxysterols that are ligands for LXR are also sulfonated by these enzymes (Fuda et al, 2007;Cook et al, 2009). Although cholecalciferol, produced from 7DHC in the skin, was not an efficient substrate (Xiangrong et al, 2000), desmosterol, 7DHC, and other postsqualene metabolites can be sulfonated (Masse et al, 1982;Axelson, 1987;Hu et al, 2015). Based on our findings, it would be interesting to determine whether any of these compounds are also endogenous substrates for SULT1C2.…”

“…Among postsqualene metabolites, activation of LXR by endogenous oxysterols regulates various aspects of cholesterol homeostasis (Janowski et al, 1996;Janowski et al, 1999;Wong et al, 2008;Zhao and DahlmanWright, 2010) whereas methyl sterols, produced from lanosterol have meiosis-stimulating activity (Byskov et al, 1995). Finally, desmosterol and other postsqualene metabolites have been linked to T H 17 lymphocyte differentiation through activation of retinoic acid-related orphan receptor g (Hu et al, 2015;Santori et al, 2015).…”

Nutrient sensing, signal transduction and immune responses

“…This is because changes in flux through the cholesterol biosynthetic pathway impact directly upon type 1 interferon signalling; decreased synthesized cholesterol in the ER results in the activation of STING/TBK1 signalling to induce IRF3 activity and the expression of interferon regulated genes ( Figure 4B) [136]. Another reason why flux through the cholesterol biosynthetic pathway is likely to be important is because intermediates in this pathway can act as agonists for RORγt transcription factors and so impact upon the differentiation of Th17 CD4 T cells [137,138].…”