Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand
Open accessAbstract
T-helper cells that produce interleukin-17 (T(H)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 α and γt (RORα and RORγt, 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 RORα and RORγt and which inhibits T(H)17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of RORα and RORγt, 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 T(H)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 T(H)17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Our data demonstrate the feasibility of targeting the orphan receptors RORα and RORγt to inhibit specifically T(H)17 cell differentiation and function, and indicate that this novel class of compound has potential utility in the treatment of autoimmune diseases.
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SR1001 is a high-affinity synthetic ligand that specifically binds to the ligand-binding domains of both RORα and RORγt.
“SR1001 is a high-affinity synthetic ligand that specifically binds to the ligand-binding domains of both RORα and RORγt [69].”
From Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain (2022) · cites this paper as [69]
The binding-assay passage (section labeled Abstract; no page given) reports selective, nanomolar-affinity binding of SR1001 to RORα and RORγ. The HDX passage examines binding to the RORγ ligand-binding domain. Our copy does not explicitly demonstrate binding to RORγt specifically or localize RORα binding to its ligand-binding domain. (LLM, conf=0.84)
Experimental — accuracy not yet measuredRORα and RORγt play indispensable roles in the differentiation of naïve CD4+ T cells into effector Th17 cells.
“The nuclear receptors retinoic acid receptor-related orphan receptors (RORs) α and γt play indispensable roles in the differentiation of naïve CD4+ T cells into effector Th17 cells.”
From Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain (2022) · cites this paper as [69]
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- Authors
- 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.
- Affiliations
- Scripps Research Institute (US)
- University of Arkansas for Medical Sciences (US)
- Corresponding author
- Burris, Thomas P.
- ORCID
- Venue
- Nature
- Published
- 2011-04
- Volume
- 472
- Issue
- 7344
- Pages
- 491-494
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3148894
- OpenAlex
- W2047756822
- Cited by
- 508
- References
- 25
- Citations by year
- 2026: 17 · 2025: 20 · 2024: 18 · 2023: 26 · 2022: 32 · 2021: 31 · 2020: 31 · 2019: 28 · 2018: 26 · 2017: 40 · 2016: 41 · 2015: 55 · 2014: 42 · 2013: 44 · 2012: 37
- FWCI
- 20.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (5u54mh074404-03)
- National Institute of Mental Health (R01MH092769, U54MH084512, MH-084512, U54-MH074404)
- National Institute of General Medical Sciences (GM084041, R01GM084041)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK080201, F32DK088499, R24DK089984, R01DK080201, DK089984, DK088499)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Th17 cells, RORγt, RORα, inverse agonists, IL-17, autoimmunity, multiple sclerosis, experimental encephalomyelitis, cardiac glycosides, digoxin, ligand-binding domain, corepressors, transcriptional coactivator
- MeSH terms
- Animals, Cell Differentiation, Humans, Interleukins, Ligands, Mice, Inbred C57BL, Models, Molecular, Sulfonamides, Thiazoles, Autoimmunity, Interleukin-17, Mice, Drug Inverse Agonism, Nuclear Receptor Subfamily 1, Group F, Member 1, Nuclear Receptor Subfamily 1, Group F, Member 3, HEK293 Cells, Th17 Cells
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