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Oxysterols Are Agonist Ligands of Rorγt and Drive Th17 Cell Differentiation

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Oxysterols Are Agonist Ligands of Rorγt and Drive Th17 Cell Differentiation Oxysterols are agonist ligands of RORγt and drive Th17 cell differentiation Pejman Soroosha,1, Jiejun Wua,1, Xiaohua Xuea,1, Jiao Songa, Steven W. Suttona, Marciano Sablada, Jingxue Yua, Marina I. Nelenb, Xuejun Liua, Glenda Castroa, Rosa Lunaa, Shelby Crawforda,2, Homayon Baniea, Rose A. Dandridgeb, Xiaohu Denga, Anton Bittnera, Chester Kueia, Mandana Tootoonchia, Natasha Rozenkrantsa, Krystal Hermana, Jingjin Gaoa, Xia V. Yanga,3, Kacey Sachena,4, Karen Ngoa, Wai-Ping Fung-Leunga, Steven Nguyena, Aimee de Leon-Tabaldoa, Jonathan Blevitta, Yan Zhanga, Maxwell D. Cummingsb, Tadimeti Raoa, Neelakandha S. Mania, Changlu Liua, Murray McKinnonb, Marcos E. Millaa, Anne M. Fouriea, and Siquan Suna,5 aJanssen Research and Development, LLC, San Diego, CA 92121; and bJanssen Research and Development, Spring House, PA 19002 Edited by Peter S. Kim, Stanford University School of Medicine, Stanford, CA, and approved July 10, 2014 (received for review December 10, 2013) The RAR-related orphan receptor gamma t (RORγt) is a nuclear and activates RORγt may, therefore, offer critical insights into + receptor required for generating IL-17–producing CD4 Th17 T the rational design of RORγt modulators to block pathogenic cells, which are essential in host defense and may play key path- IL-17–producing cells in disease. ogenic roles in autoimmune diseases. Oxysterols elicit profound Oxysterols are oxygenated derivatives of cholesterol or by- effects on immune and inflammatory responses as well as on cho- products of cholesterol synthesis (6–9). Some oxysterols serve as lesterol and lipid metabolism. Here, we describe the identification key intermediates for bile acid and steroid synthesis and function of several naturally occurring oxysterols as RORγt agonists. The as signaling molecules or receptor ligands modulating cell pro- most potent and selective activator for RORγtis7β, 27-dihydroxy- liferation and apoptosis, lipid and cholesterol synthesis, trans- cholesterol (7β, 27-OHC). We show that these oxysterols reverse portation and metabolism, and immune responses. For example, the inhibitory effect of an RORγt antagonist, ursolic acid, in RORγ- certain oxysterols have been shown to serve as endogenous or RORγt-dependent cell-based reporter assays. These ligands bind ligands of EBI2 receptor (10, 11), activate the liver X receptor directly to recombinant RORγ ligand binding domain (LBD), pro- (12), function as a selective estrogen receptor modulator (13), mote recruitment of a coactivator peptide, and reduce binding of or affect Hedgehog signaling by binding to the Smoothened molecule (14). In addition, several oxysterols were previously a corepressor peptide to RORγ LBD. In primary cells, 7β, 27-OHC shown to function as RORγ or RORα inverse agonists (such and 7α, 27-OHC enhance the differentiation of murine and human – γ as 7-hydroxylated oxysterols) or 24(S)-OHC agonists (such as IL-17 producing Th17 cells in an ROR t-dependent manner. Impor- 25-OHC) (4, 15, 16). However, their role as endogenous RORγ, tantly, we showed that Th17, but not Th1 cells, preferentially pro- RORγt, or RORα ligands in vivo was not clearly shown. β duce these two oxysterols. In vivo, administration of 7 , 27-OHC We have identified a number of naturally occurring oxysterols in mice enhanced IL-17 production. Mice deficient in CYP27A1, as RORγt agonists. Although we cannot exclude at present the a key enzyme in generating these oxysterols, showed significant γ + + existence of additional endogenous agonists of ROR t, here reduction of IL-17–producing cells, including CD4 and γδ T cells, we show that two 7, 27-dihydroxycholesterols (i.e., 7β, 27-OHC similar to the deficiency observed in RORγt knockout mice. Our and 7α, 27-OHC) are strong candidates as endogenous RORγt results reveal a previously unknown mechanism for selected oxy- sterols as immune modulators and a direct role for CYP27A1 in Significance generating these RORγt agonist ligands, which we propose as RORγt endogenous ligands, driving both innate and adaptive IL-17– Because of its essential role in driving IL-17 production, the or- dependent immune responses. phan nuclear receptor RAR-related orphan receptor gamma t INFLAMMATION (RORγt) represents a potential therapeutic target for autoimmune IMMUNOLOGY AND – + L-17 producing CD4 Th17 cells are essential in protective diseases. Here, we present evidence that 7β, 27-dihydrox- Iimmunity against extracellular bacterial and fungal infections ycholesterol (7β,27-OHC)and7α, 27-OHC are RORγtagonist but also, play key pathogenic roles in autoimmune diseases, such ligands and may serve as potential endogenous RORγt ligands + as psoriasis and multiple sclerosis. RAR-related orphan receptor in promoting the differentiation of mouse and human CD4 gamma t (RORγt) is an orphan nuclear receptor expressed in Th17 cells. These findings may not only facilitate rational de- + several immune cell types, including CD4 Th17 cells. Because sign of RORγt modulators but also, provide insights into addi- of its essential role in driving IL-17 production, RORγt repre- tional targets for inhibiting IL-17 production. sents a potential target for therapeutic intervention, and a num- ber of antagonists have been published that inhibited Th17 cell Author contributions: P.S., J.W., X.X., J.S., T.R., N.S.M., M.M., A.M.F., and S.S. designed differentiation (1–3). However, the nature of RORγt endog- research; P.S., J.W., X.X., J.S., S.W.S., M.S., J.Y., M.I.N., G.C., R.L., S.C., H.B., R.A.D., X.D., A.B., C.K., M.T., N.R., K.H., J.G., X.V.Y., K.S., K.N., W.-P.F.-L., S.N., A.d.L.-T., J.B., Y.Z., and enous ligands remains unknown, although accumulating evi- C.L. performed research; X.D., N.S.M., and C.L. contributed new reagents/analytic tools; dence suggested the existence of such ligands. For example, P.S., J.W., X.X., J.S., S.W.S., J.Y., M.I.N., X.L., R.L., S.C., H.B., M.D.C., and S.S. analyzed data; crystal structures of the ligand binding domain of RORγ clearly and P.S., J.W., X.X., M.I.N., X.D., C.K., M.E.M., A.M.F., and S.S. wrote the paper. showed a well-defined pocket that could accommodate a cho- The authors declare no conflict of interest. lesterol or 25-hydroxycholesterol (OHC) molecule (4). Purified This article is a PNAS Direct Submission. + naïve CD4 T cells can be activated in culture to differentiate Freely available online through the PNAS open access option. into IL-17–producing cells, suggesting that these cells have the 1P.S., J.W., and X.X. contributed equally to this work. capacity to produce endogenous RORγt ligand(s). In addition, 2Present address: Private address, San Diego, CA 92130. + IL-17–producing mouse RORγt innate lymphoid cells, believed 3Present address: Regulus Therapeutics, San Diego, CA 92121. to be essential in orchestrating immunity at mucosal sites, in- 4Present address: Takeda San Diego Inc., San Diego, CA 92121. cluding intestine and lung, were shown to be generated in vivo 5To whom correspondence should be addressed. Email: [email protected]. under germfree conditions (5). Identification of the endogenous This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. agonist ligand(s) and understanding of how the ligand engages 1073/pnas.1322807111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1322807111 PNAS | August 19, 2014 | vol. 111 | no. 33 | 12163–12168 Downloaded by guest on September 28, 2021 + agonists driving IL-17 production in CD4 Th17 cells as well as 7-KC, 25-OHC, 24(S), 25-EC, and 24(S)-OHC (15, 16) showed + other IL-17–producing innate cells, such as γδ T cells. weak to moderate agonist activity. Cholestenoic acid derivatives of the 27-hydroxylated sterols displayed minimal agonist activity Results (SI Appendix, Table S1), indicating that the hydroxyl group at RORγt Agonist Activity of Selected Oxysterols. To identify potential carbon 27 is required for RORγt agonism. We next tested se- RORγt agonists, we screened a panel of naturally occurring lected oxysterols, including all four 27-OHCs, in cell-based full- oxysterols and a few other compounds (SI Appendix, Tables S1 length human RORγ- or RORγt-dependent reporter assays. One and S2) for their agonist activity in reversing the inhibitory effect clear exception was 7-keto, 27-OHC, which was largely inactive of ursolic acid (UA), an RORγt antagonist (3). We first used a in those two assays, whereas other 27-OHCs were active, and cell-based RORγ-dependent reporter assay, in which the DNA- there was no apparent difference between RORγ- and RORγt- binding domain of GAL4 was fused to the ligand binding dependent assays (SI Appendix, Fig. S1). domain (LBD) of human RORγ. This construct was transiently To establish the selectivity of the RORγt-active 27-OHCs, we expressed in HEK293T cells and showed constitutive activity in tested them for potential agonist activity in several nuclear re- driving luciferase reporter gene expression. Because RORγt and ceptor (NR) reporter assays (SI Appendix, Fig. S2). While the related isotype, RORγ, share the same LBD, such an assay 27-OHC showed weak activity for LXRα and 27-OHC and 7- potentially allowed detection of agonists for both receptors. A keto, 27-OHC showed moderate activity for LXRβ,7β, 27-OHC number of oxysterols showed significant agonist activity, with and 7α, 27-OHC were inactive up to 30 μM. 27-OHC also showed 27-OHC, 7β, 27-OHC, and 7-keto, 27-OHC being the most po- weak activity for ERβ,but7β, 27-OHC, 7α, 27-OHC, and 7-keto, tent and efficacious (Fig. 1A and SI Appendix, Tables S1 and S2). 27-OHC were inactive against ERα or ERβ.
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