A novel RORγt inhibitor is a potential therapeutic agent for the topical treatment of psoriasis with low risk of thymic aberrations

Imura, Chihiro; Ueyama, Azumi; Sasaki, Yasutaka; Shimizu, Masaya; Furue, Yoko; Tai, Nobuyuki; Tsujii, Kenichiro; Katayama, Kazufumi; Okuno, Takayuki; Shichijo, Michitaka; Yasui, Kiyoshi; Yamamoto, Mina

doi:10.1016/j.jdermsci.2019.03.002

Cited by 27 publications

(18 citation statements)

References 24 publications

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“…However, RORγt also is mainly expressed in DP thymocytes subpopulations [42,43], and Rorc-deficient (Rorc-/-) in mice would increase thymocyte apoptosis, alter CD4/CD8 subpopulation in the thymus, leading to the emergence of T lymphoma in the thymus [17,18,41,44,45]. Generous studies showed that small molecule agents as RORγt inhibitors had an inhibition for the functions of Th17 cells [22,27,28,46], such as SR1001, digoxin, and ML209, but had others side effects in thymus, including DP thymocytes apoptosis, anti-apoptotic genes downregulated and the induction thymic lymphoma [23,47]. In this study, we found that TTP disturbed the functions of Th17 cells, however, it did not affect the numbers and frequency of CD4 + CD8 + DP thymocytes population, and the total numbers of thymocytes had no significant difference with control group (Fig.…”

Section: Discussionmentioning

confidence: 99%

5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine derivative attenuates lupus nephritis with less effect to thymocyte development

Wei

Zhou

Chen

et al. 2020

Preprint

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Objective To investigate the effect of a RORγt inhibitor, 5,6,7,8-tetrahydrobenzo [4,5]thieno [2,3-d]pyrimidine derivative (TTP), on the therapy of lupus nephritis and the safe risk on thymocytes development. Methods BALB/C female mice were 2 months for pristane-induced mice model of lupus nephritis with the treatment of vehicle, prednisone acetate, and TTP. And 4-week-old BALB/C female mice were used for studying the development of thymus with the treatment of vehicle and TTP. Results TTP repressed the development of Th17 cells and ameliorated the autoimmune disease manifestation in a pristine induced lupus nephritis mouse model. The treatment of TTP in mice didn’t interfere with thymocyte development, including total thymocyte numbers and proportion of CD4+CD8+ double-positive populations in thymus, and had no substantial effects on thymoma incidence. Surface plasmon resonance identified the TTP had stronger affinity with full length RORγt protein compared the truncated RORγt LBD region, indicated TTP binding to RORγt beyond LBD region. Molecular docking computation showed the best binding pocket of TTP to RORγt located in the hinge region of RORγt. Conclusion As a RORγt inhibitor, TTP had potential to develop drug for treating Th17-cell-mediated autoimmune diseases with low safety risk for thymocyte development.

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Section: Discussionmentioning

confidence: 99%

5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine derivative attenuates lupus nephritis with less effect to thymocyte development

Wei

Zhou

Chen

et al. 2020

Preprint

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“…Psoriatic skin was reported to have increased numbers of CD11c + myeloid DCs in the dermis,which has an important role in the psoriasis pathogenesis [23] . Retinoic acid receptor-related orphan receptor gamma-t (RORγt) has critical role in the differentiation, maintenance and function of IL-17-producing cells and is a highly attractive target for the treatment of IL-17-mediated autoimmune diseases, particularly psoriasis [24] . In this study, we observed presence of RORγt positive cells only in the dermis of model group, while in health controls and the GNY decoction treated groups negligible levels of RORγt positive cells were present.…”

Section: Discussionmentioning

confidence: 99%

Gancao Nurish-Yin Decoction Ameliorates Imiquimod-Induced Psoriasis-Like Skin Lesions and Inflammation in Mice

Chen¹,

Wu²,

Chen³

et al. 2020

Preprint

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BackgroundPsoriasis is an autoimmune skin disease with a high clinical prevalence, which is often poses treatment difficulties. In this study, we tested whether Gancao nurish-Yin (GNY) decoction is effective for treating mice with imiquimod (IMQ)-induced psoriasis-like skin lesions. MethodsMice were divided into 4 groups including healthy control group, model group (IMQ-induced psoriasis mice), and two psoriasis induced groups of mice treated with GNY-2.5g/kg and GNY-5g/kg given in the drinking water (n = 8/group). Psoriasis area and severity index (PASI) was used to monitor psoriatic symptoms. H&E staining of dermis and baker’s scores were used to evaluate disease severity. Inflammatory cells positive for Gr-1, CD11c, RORγt and TGF-β were counted by using immunohistochemistry or immunofluorescence staining methods. Flow cytometry was used to analyse CD4+CD17+ Th17 cells, and CD25+Foxp3+ Tregs within splenocyte cell population. Relative mRNA expression of IL-6, IL-10, IL-17A, IL-22, IL-23, TNF-ɑ, TGF-β and AMPKɑ1 in the dermis was was semi-quatified using qPCR. ResultsCompared to model group, GNY decoction treated mice, at both the concentrations, improved morphological features, as demonstrated by PASI scores and decreased levels of hyperproliferating keratinocytes. GNY decoction at a higher concentration significantly decreased Gr-1, CD11c, RORγt and TGF-β positive cells in the dermis as well as the differentiated CD4+CD17+ Th17 cells, whereas, CD25+Foxp3+ Tregs were increased in the spleen, mainly with low dose GNY decoction. Furthermore, relative mRNA expression of IL-6, IL-10, IL-17A, IL-22, IL-23, TNF-ɑ, TGF-β and AMPKɑ1 within dermis were elevated in mice from IMQ model group, which were significantly recduced in mice treated with GNY decoction at GNY-5g/kg concentration.ConclusionHere we demonstrate disease ameliorating effects of GNY decoction in IMQ-induced psoriasis-like skin lesions in mice, which could form basis for considering GNY decoction for treatment of psoriasis patients.

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“…Because of this liver toxicity, the initially planned third clinical trial of VTP-43742 was discontinued [ 79 ]. Although the phase 1 clinical trial of GSK2981278 ointment (selective RORγ inverse agonist) showed a lack of efficacy, new topical RORγt inhibitors may be a potential candidate for the treatment of psoriasis [ 80 , 81 ].…”

Section: Treatmentmentioning

confidence: 99%

New Treatment Addressing the Pathogenesis of Psoriasis

Tokuyama

Mabuchi

2020

IJMS

190

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Psoriasis is an immune cell-mediated inflammatory skin disease. The interleukin (IL)23/IL17 axis plays an important role in the development of psoriasis. The effectiveness of biologic treatments such as tumor necrosis factor (TNF)α inhibitors (infliximab, adalimumab, certolizumab pegol), IL23 inhibitors (ustekinumab, guselkumab, tildrakizumab, risankizumab), and IL17 inhibitors (secukinumab, ixekizumab, brodalumab) have verified these findings. Immune-related cells such as dendritic cells (DCs) and macrophages, in addition to Toll-like receptors and cytokines such as interferon (IFN)α, TNFα, IFNɤ, IL12, IL22, IL23, and IL17, are related to the pathogenesis of psoriasis. Here, we first review new insights regarding the pathogenesis of psoriasis, as it relates to DCs, Langerhans cells, macrophages, the signal transducer and activator of transcription 3 pathway, and aryl hydrocarbon receptor in cutaneous vascular endothelial cells. Based on these findings, we summarize currently available oral treatments and biologics. Furthermore, we describe a new treatment option including Janus kinase inhibitor, tyrosine kinase 2 inhibitor, modulator of sphingosine 1-phosphate receptor 1, and Rho-associated kinase 2 inhibitor.

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A novel RORγt inhibitor is a potential therapeutic agent for the topical treatment of psoriasis with low risk of thymic aberrations

Cited by 27 publications

References 24 publications

5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine derivative attenuates lupus nephritis with less effect to thymocyte development

5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine derivative attenuates lupus nephritis with less effect to thymocyte development

Gancao Nurish-Yin Decoction Ameliorates Imiquimod-Induced Psoriasis-Like Skin Lesions and Inflammation in Mice

New Treatment Addressing the Pathogenesis of Psoriasis

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