Suppression of TH 17 differentiation and autoimmunity by a synthetic ROR ligand

Laura A. Solt, Naresh Kumar, Philippe Nuhant, Yongjun Wang, Janelle L. Lauer, Jin Liu, Monica A. Istrate, Theodore M. Kamenecka, William R. Roush, Dušica Vidović, Stephan C. Schürer, Jihong Xu, Gail Wagoner, Paul D. Drew, Patrick R. Griffin, Thomas P. Burris

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317 Scopus citations

Abstract

T-helper cells that produce interleukin-17 (TH 17 cells) are a recently identified CD4+ T-cell subset with characterized pathological roles in autoimmune diseases. The nuclear receptors retinoic-acid-receptor-related orphan receptors Î ± and Î 3t (RORÎ ± and RORÎ 3t, respectively) have indispensible roles in the development of this cell type. Here we present SR1001, a high-affinity synthetic ligand-the first in a new class of compound-that is specific to both ROR ± and ROR 3t and which inhibits TH 17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of RORÎ ± and ROR 3t, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix 12 and leads to diminished affinity for co-activators and increased affinity for co-repressors, resulting in suppression of the receptors-™ transcriptional activity. SR1001 inhibited the development of murine TH 17 cells, as demonstrated by inhibition of interleukin-17A gene expression and protein production. Furthermore, SR1001 inhibited the expression of cytokines when added to differentiated murine or human TH 17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Our data demonstrate the feasibility of targeting the orphan receptors ROR ± and RORÎ 3t to inhibit specifically TH 17 cell differentiation and function, and indicate that this novel class of compound has potential utility in the treatment of autoimmune diseases.

Original languageEnglish (US)
Pages (from-to)491-494
Number of pages4
JournalNature
Volume472
Issue number7344
DOIs
StatePublished - Apr 28 2011

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    Solt, L. A., Kumar, N., Nuhant, P., Wang, Y., Lauer, J. L., Liu, J., Istrate, M. A., Kamenecka, T. M., Roush, W. R., Vidović, D., Schürer, S. C., Xu, J., Wagoner, G., Drew, P. D., Griffin, P. R., & Burris, T. P. (2011). Suppression of TH 17 differentiation and autoimmunity by a synthetic ROR ligand. Nature, 472(7344), 491-494. https://doi.org/10.1038/nature10075