|
| Status |
Public on Oct 29, 2020 |
| Title |
Genetic and pharmacological inhibition of the nuclear receptor RORa regulates Th17 driven inflammatory disorders |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Full development of IL-17 producing CD4+ T helper cells (TH17 cells) requires the transcriptional activity of both orphan nuclear receptors RORa and RORgt. Despite this evidence, RORa is considered functionally redundant to RORgt; thus, the function and therapeutic value of RORa in TH17 cells remains underexplored. Using mouse models of autoimmune and chronic inflammation, we show that expression of RORa is required for TH17 cell pathogenicity. T-cell specific deletion of RORa reduced the development of experimental autoimmune encephalomyelitis (EAE) and colitis. Reduced inflammation was associated with decreased TH17 cell development, lower expression of tissue-homing chemokine receptors and integrins, and increased frequencies of Foxp3+ T regulatory (Treg) cells. Importantly, inhibition of RORa with a selective small molecule antagonist largely phenocopied our genetic data, potently suppressing the in vivo development of both chronic/progressive and relapsing/remitting EAE but had no effect on overall thymic cellularity. Furthermore, use of the RORa antagonist effectively inhibited human TH17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORa acts independently of RORgt in programming TH17 pathogenicity and identifies RORa as a safer and more selective therapeutic target for the treatment of TH17-mediated autoimmunity.
|
| |
|
| Overall design |
4 samples; 2 replicates per condition
|
| |
|
| Contributor(s) |
Solt LA |
| Citation(s) |
33397953 |
| |
| Submission date |
Oct 28, 2020 |
| Last update date |
Jan 19, 2021 |
| Contact name |
Laura A Solt |
| E-mail(s) |
lsolt@scripps.edu
|
| Organization name |
The Scripps Research Institute
|
| Department |
Immunology and Microbiology
|
| Street address |
130 Scripps Way
|
| City |
Jupiter |
| State/province |
FL |
| ZIP/Postal code |
33458 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
|
| Samples (4)
|
|
| Relations |
| BioProject |
PRJNA672951 |
| SRA |
SRP289490 |
Less...
More...