A Novel Selective Sphingosine Kinase 2 Inhibitor, HWG-35D, Ameliorates the Severity of Imiquimod-Induced Psoriasis Model by Blocking Th17 Differentiation of Naïve CD4 T Lymphocytes

A Novel Selective Sphingosine Kinase 2 Inhibitor, HWG-35D, Ameliorates the Severity of Imiquimod-Induced Psoriasis Model by Blocking Th17 Differentiation of Naïve CD4 T Lymphocytes

Sphingosine kinases (SK) catalyze the phosphorylation of sphingosine to generate sphingosine-1-phosphate. Two isoforms of SK (SK1 and SK2) exist in mammals. Previously, we showed the beneficial effects of SK2 inhibition, using ABC294640, in a psoriasis mouse model. However, ABC294640 also induces th...

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Main Authors: Sun-Hye Shin, Hee-Yeon Kim, Hee-Soo Yoon, Woo-Jae Park, David R. Adams, Nigel J. Pyne, Susan Pyne, Joo-Won Park
Format: Article
Language:English
Published: MDPI AG 2020-11-01
Series:International Journal of Molecular Sciences
Subjects:
psoriasis
HWG-35D
sphingosine kinase
sphingosine-1-phosphate
T helper type 17 differentiation
Online Access:https://www.mdpi.com/1422-0067/21/21/8371
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spelling doaj-1f4ba4832f314af19f71c708a3affd1c2020-11-25T04:05:07ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-11-01218371837110.3390/ijms21218371A Novel Selective Sphingosine Kinase 2 Inhibitor, HWG-35D, Ameliorates the Severity of Imiquimod-Induced Psoriasis Model by Blocking Th17 Differentiation of Naïve CD4 T LymphocytesSun-Hye Shin0Hee-Yeon Kim1Hee-Soo Yoon2Woo-Jae Park3David R. Adams4Nigel J. Pyne5Susan Pyne6Joo-Won Park7Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul 07804, KoreaDepartment of Biochemistry, College of Medicine, Ewha Womans University, Seoul 07804, KoreaDepartment of Biochemistry, College of Medicine, Ewha Womans University, Seoul 07804, KoreaDepartment of Biochemistry, College of Medicine, Gachon University, Incheon 21999, KoreaSchool of Engineering & Physical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, UKStrathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UKStrathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UKDepartment of Biochemistry, College of Medicine, Ewha Womans University, Seoul 07804, KoreaSphingosine kinases (SK) catalyze the phosphorylation of sphingosine to generate sphingosine-1-phosphate. Two isoforms of SK (SK1 and SK2) exist in mammals. Previously, we showed the beneficial effects of SK2 inhibition, using ABC294640, in a psoriasis mouse model. However, ABC294640 also induces the degradation of SK1 and dihydroceramide desaturase 1 (DES1). Considering these additional effects of ABC294640, we re-examined the efficacy of SK2 inhibition in an IMQ-induced psoriasis mouse model using a novel SK2 inhibitor, HWG-35D, which exhibits nM potency and 100-fold selectivity for SK2 over SK1. Topical application of HWG-35D ameliorated IMQ-induced skin lesions and normalized the serum interleukin-17A levels elevated by IMQ. Application of HWG-35D also decreased skin mRNA levels of interleukin-17A, K6 and K16 genes induced by IMQ. Consistent with the previous data using ABC294640, HWG-35D also blocked T helper type 17 differentiation of naïve CD4<sup>+</sup> T cells with concomitant reduction of SOCS1. Importantly, HWG-35D did not affect SK1 or DES1 expression levels. These results reaffirm an important role of SK2 in the T helper type 17 response and suggest that highly selective and potent SK2 inhibitors such as HWG-35D might be of therapeutic use for the treatment of psoriasis.https://www.mdpi.com/1422-0067/21/21/8371psoriasisHWG-35Dsphingosine kinasesphingosine-1-phosphateT helper type 17 differentiation
collection DOAJ
language English
format Article
sources DOAJ
author Sun-Hye Shin
Hee-Yeon Kim
Hee-Soo Yoon
Woo-Jae Park
David R. Adams
Nigel J. Pyne
Susan Pyne
Joo-Won Park
spellingShingle Sun-Hye Shin
Hee-Yeon Kim
Hee-Soo Yoon
Woo-Jae Park
David R. Adams
Nigel J. Pyne
Susan Pyne
Joo-Won Park
A Novel Selective Sphingosine Kinase 2 Inhibitor, HWG-35D, Ameliorates the Severity of Imiquimod-Induced Psoriasis Model by Blocking Th17 Differentiation of Naïve CD4 T Lymphocytes
International Journal of Molecular Sciences
psoriasis
HWG-35D
sphingosine kinase
sphingosine-1-phosphate
T helper type 17 differentiation
author_facet Sun-Hye Shin
Hee-Yeon Kim
Hee-Soo Yoon
Woo-Jae Park
David R. Adams
Nigel J. Pyne
Susan Pyne
Joo-Won Park
author_sort Sun-Hye Shin
title A Novel Selective Sphingosine Kinase 2 Inhibitor, HWG-35D, Ameliorates the Severity of Imiquimod-Induced Psoriasis Model by Blocking Th17 Differentiation of Naïve CD4 T Lymphocytes
title_short A Novel Selective Sphingosine Kinase 2 Inhibitor, HWG-35D, Ameliorates the Severity of Imiquimod-Induced Psoriasis Model by Blocking Th17 Differentiation of Naïve CD4 T Lymphocytes
title_full A Novel Selective Sphingosine Kinase 2 Inhibitor, HWG-35D, Ameliorates the Severity of Imiquimod-Induced Psoriasis Model by Blocking Th17 Differentiation of Naïve CD4 T Lymphocytes
title_fullStr A Novel Selective Sphingosine Kinase 2 Inhibitor, HWG-35D, Ameliorates the Severity of Imiquimod-Induced Psoriasis Model by Blocking Th17 Differentiation of Naïve CD4 T Lymphocytes
title_full_unstemmed A Novel Selective Sphingosine Kinase 2 Inhibitor, HWG-35D, Ameliorates the Severity of Imiquimod-Induced Psoriasis Model by Blocking Th17 Differentiation of Naïve CD4 T Lymphocytes
title_sort novel selective sphingosine kinase 2 inhibitor, hwg-35d, ameliorates the severity of imiquimod-induced psoriasis model by blocking th17 differentiation of naïve cd4 t lymphocytes
publisher MDPI AG
series International Journal of Molecular Sciences
issn 1661-6596
1422-0067
publishDate 2020-11-01
description Sphingosine kinases (SK) catalyze the phosphorylation of sphingosine to generate sphingosine-1-phosphate. Two isoforms of SK (SK1 and SK2) exist in mammals. Previously, we showed the beneficial effects of SK2 inhibition, using ABC294640, in a psoriasis mouse model. However, ABC294640 also induces the degradation of SK1 and dihydroceramide desaturase 1 (DES1). Considering these additional effects of ABC294640, we re-examined the efficacy of SK2 inhibition in an IMQ-induced psoriasis mouse model using a novel SK2 inhibitor, HWG-35D, which exhibits nM potency and 100-fold selectivity for SK2 over SK1. Topical application of HWG-35D ameliorated IMQ-induced skin lesions and normalized the serum interleukin-17A levels elevated by IMQ. Application of HWG-35D also decreased skin mRNA levels of interleukin-17A, K6 and K16 genes induced by IMQ. Consistent with the previous data using ABC294640, HWG-35D also blocked T helper type 17 differentiation of naïve CD4<sup>+</sup> T cells with concomitant reduction of SOCS1. Importantly, HWG-35D did not affect SK1 or DES1 expression levels. These results reaffirm an important role of SK2 in the T helper type 17 response and suggest that highly selective and potent SK2 inhibitors such as HWG-35D might be of therapeutic use for the treatment of psoriasis.
topic psoriasis
HWG-35D
sphingosine kinase
sphingosine-1-phosphate
T helper type 17 differentiation
url https://www.mdpi.com/1422-0067/21/21/8371
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