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.

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.

• Authors: Sun-Hye Shin, Hee-Yeon Kim, Hee-Soo Yoon, Woo-Jae Park, David R Adams, Nigel J Pyne, Susan Pyne, Joo-Won Park
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 21 (Nov 08 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33171607 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Il17a protein, mouse
• Interleukin-17
• RNA, Messenger
• Phosphotransferases (Alcohol Group Acceptor)
• Sphk1 protein, mouse
• sphingosine kinase 2, mouse
• Imiquimod

Topics

• Animals
• CD4-Positive T-Lymphocytes (drug effects, immunology, pathology)
• Cell Differentiation (drug effects, immunology)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Humans
• Imiquimod (toxicity)
• In Vitro Techniques
• Interleukin-17 (blood, genetics)
• Male
• Mice
• Mice, Inbred C57BL
• Phosphotransferases (Alcohol Group Acceptor) (antagonists & inhibitors, metabolism)
• Psoriasis (chemically induced, drug therapy, immunology)
• RNA, Messenger (genetics, metabolism)
• Skin (drug effects, immunology, metabolism)
• Th17 Cells (drug effects, immunology, pathology)