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

Sun-Hye Shin, Hee-Yeon Kim, Hee-Soo Yoon, Woo-Jae Park, David R Adams, Nigel J. Pyne, Susan Pyne, Joo-Won Park

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Abstract

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+ 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.

Original languageEnglish
Article number8371
Number of pages17
JournalInternational Journal of Molecular Sciences
Volume21
Issue number21
DOIs
Publication statusPublished - 8 Nov 2020

Keywords

  • psoriasis
  • HWG-35D
  • Sphingosine kinase
  • Sphingosine-1-phosphate
  • T helper type 17 differentiation

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