Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand

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

doi:10.1038/nature10075

Cited by 449 publications

(426 citation statements)

References 25 publications

(26 reference statements)

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“…Binding of SR1001 results in a conformational change that decreases the affinity of RORa for coactivators and increases its affinity for corepressors, leading to inhibition of RORa activity (35,36). Treatment of SR1001 suppressed pathological retinal neovascularization in the OIR model in our previous study (25).…”

Section: Rora Negatively Regulated Sema3e Promoter-driven Transcriptionmentioning

confidence: 99%

“…RORa regulation of Sema3e transcription was also validated by treatment with a synthetic inverse agonist of RORa/g, SR1001, which can bind directly to the ligandbinding domain of RORa (35,36). Binding of SR1001 results in a conformational change that decreases the affinity of RORa for coactivators and increases its affinity for corepressors, leading to inhibition of RORa activity (35,36).…”

Section: Rora Negatively Regulated Sema3e Promoter-driven Transcriptionmentioning

confidence: 99%

“…5C). In addition, we evaluated whether AAV2-shSema3e may reverse the pathological neovascularization suppressed by a synthetic inverse agonist of RORa/g, SR1001 (35), in OIR. SR1001 treatment increased Sema3e expression in the retinas, confirming that RORa inhibition induces Sema3e (Fig.…”

Section: Rora-sema3e Axis Regulated Neurovascular Interaction To Affementioning

confidence: 99%

“…HEK293T cells were transiently cotransfected with pCDH1-RORa-Flag, WT or mutant pGL2-Sema3e promoter reporter, or Renilla luciferase vector alone as control. SR1001 was synthesized at the Scripps Research Institute as previously described (34)(35)(36). SR1001 was dissolved in DMSO, and the pretransfected HEK293T cells were treated overnight.…”

Section: Luciferase Reporter Assaymentioning

confidence: 99%

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RORα modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis

et al. 2017

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Pathological proliferation of retinal blood vessels commonly causes vision impairment in proliferative retinopathies, including retinopathy of prematurity. Dysregulated crosstalk between the vasculature and retinal neurons is increasingly recognized as a major factor contributing to the pathogenesis of vascular diseases. Class 3 semaphorins (SEMA3s), a group of neuron-secreted axonal and vascular guidance factors, suppress pathological vascular growth in retinopathy. However, the upstream transcriptional regulators that mediate the function of SEMA3s in vascular growth are poorly understood. Here we showed that retinoic acid receptor-related orphan receptor a (RORa), a nuclear receptor and transcription factor, is a novel transcriptional regulator of SEMA3E-mediated neurovascular coupling in a mouse model of oxygen-induced proliferative retinopathy. We found that genetic deficiency of RORa substantially induced Sema3e expression in retinopathy. Both RORa and SEMA3E were expressed in retinal ganglion cells. RORa directly bound to a specific ROR response element on the promoter of Sema3e and negatively regulated Sema3e promoter-driven luciferase expression. Suppression of Sema3e using adeno-associated virus 2 carrying short hairpin RNA targeting Sema3e promoted disoriented pathological neovascularization and partially abolished the inhibitory vascular effects of RORa deficiency in retinopathy. Our findings suggest that RORa is a novel transcriptional regulator of SEMA3E-mediated neurovascular coupling in pathological retinal angiogenesis.-Sun, Y., Liu, C.-H., Wang, Z., Meng, S. S., Burnim, S. B., SanGiovanni, J. P., Kamenecka, T. M., Solt, L. A., Chen, J. RORa modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis. FASEB J. 31, 4492-4502 (2017). www.fasebj.org

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Section: Rora Negatively Regulated Sema3e Promoter-driven Transcriptionmentioning

confidence: 99%

Section: Rora Negatively Regulated Sema3e Promoter-driven Transcriptionmentioning

confidence: 99%

Section: Rora-sema3e Axis Regulated Neurovascular Interaction To Affementioning

confidence: 99%

Section: Luciferase Reporter Assaymentioning

confidence: 99%

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RORα modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis

et al. 2017

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“…However, little is known about the involvement of RORγt in thrombocytopenia and autoimmune hemolytic anemia. Solt et al [33] have reported that synthetic ROR ligand suppresses Th17 differentiation and autoimmunity. These findings suggest that therapy involving the regulation of ROR might be of potential use in the treatment of autoimmune diseases.…”

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confidence: 99%

Overexpression of RORγt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice

et al. 2012

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Retinoic acid related orphan receptor gamma-t (RORγt) is known to be a master regulator of Th17-cell development. In this study, we generated RORγt-overexpressing transgenic (RORγt Tg) mice in which transgene expression was driven by the CD2 promoter, and found that these mice developed polyclonal plasmacytosis and autoantibody production. RORγt Tg mice were generated on a C57BL/6 background, and also were intercrossed with BALB/c mice. BALB/c F1 (BALB/F1) RORγt Tg mice developed massive polyclonal plasmacytosis, and had shorter life spans. Splenomegaly and infiltration of plasma cells into the lung were observed. Hyperglobulinemia, anti-double-stranded DNA antibodies, antierythrocyte antibodies, and anti-platelet antibodies were detected in BALB/F1 RORγt Tg mice. In the present study, polyclonal plasmacytosis in BALB/F1 RORγt Tg mice appeared to be due to the induction of excessive IL-6 production by IL-17. We detected increased numbers of CD11b + cells that produced IL-6. We also generated IL-6-deficient RORγt Tg BALB/F1 background mice, which displayed high levels of serum IL-17, but did not develop severe hyperglobulinemia. Excessive IL-6 production by several cell types, including macrophages, in BALB/F1 RORγt Tg mice, might effect the development of plasmacytosis. These results suggest that RORγt plays important roles in the development of plasmacytosis and autoantibody production. Eur. J. Immunol. 2012Immunol. . 42: 1999Immunol. -2009 Introduction CD4 + T helper (Th) cells are a subcategory of T lymphocytes that play a central role in modulating immune responses. Classically, naïve CD4 + T cells have been thought to differentiate into two cell types, Th1 and Th2 cells. This corresponds to the Th1/Th2 paradigm proposed by Mosmann et al. [1]. More recently, a third subset of Th cells, Th17 cells, has been described; this is a distinct lineage that does not share developmental pathways with either Th1 or Th2 cells [2,3]. Th17 cells are generally thought to be proinflammatory, especially through the production of 3]. Th17 cells have been shown to participate in the development of autoimmunity, and also to play an important role in host defense against infection [4]. Expression of the transcription factor retinoic acid related orphan receptor gamma-t (RORγt) is required for the differentiation of Th17 cells [5,6]. The orphan receptor RORγt is a thymusspecific isoform of RORγ [7]. A related nuclear receptor, RORα, was shown to act in synergy with RORγt to promote the differentiation of Th17 cells [8]. STAT3 is also required for full generation of the Th17 lineage [9]. The upregulation of RORγt depends on STAT3 [9], and the selective deletion of STAT3 in T cells partially abrogates the development of Th17 cells because it also abrogates the expression of RORα and RORγt [8].IL-6 is an important cytokine in the differentiation of Th17 cells. IL-6, together with TGF-β, is required to induce IL-17 expression in naïve CD4 + T cells, which are characterized by the expression of RORγt [5,10,11]. Since its discovery i...

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Application of Differential Hydrogen Exchange Mass Spectrometry in Small Molecule Drug Discovery

Goswami

Marciano

Pascal

et al. 2016

Hydrogen Exchange Mass Spectrometry of Proteins

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Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand

Cited by 449 publications

References 25 publications

RORα modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis

RORα modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis

Overexpression of RORγt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice

Application of Differential Hydrogen Exchange Mass Spectrometry in Small Molecule Drug Discovery

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