S1P/S1PRs-TRPV4 axis is a novel therapeutic target for persistent pain and itch in chronic dermatitis
inyu Zhang1,2 | Yuan Zhou2 | ChangmingWang2 | JiahuiRen2 | YinWang2 |Pei Liu1 | WeimengFeng1 | XueLi2 | MingxinQi2 | YanYang2 |Chan Zhu2 | FangWang3 | YuxiangMa4 | ZongxiangTang2 | GuangYu1,2
1Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing
University of Chinese Medicine, Nanjing, China
2Key Laboratory for Chinese Medicine of Prevention and Treatment in Neurological Diseases, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China
3Department of Dermatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
4School of Life Science, China Pharmaceutical University, Nanjing, China
Abstract
Background and Purpose: While pain and itch are both commonly associated with chronic dermatitis (CD), the molecular mechanisms underlying these debilitating symptoms is not well understood. This study aims to identify novel, endogenous compounds that mediate CD-associated pain and itch.
Experimental Approach: Lesional skin of CD model mice was examined using unbiased metabolomic analysis to identify candidate pain or itch inducing compounds in CD. Sphingosine-1-phosphate (S1P) concentration in CD model skin was analysed using UPLC/MS/MS. Behaviour, calcium imaging and immunofluorescence staining were used to determine the pain and itch effects and mechanisms of the identified CD-related compounds.
Key Results: In the lesional skin of CD model mice, 136 compounds were significantly changed. These compounds are predominately associated with the sphingolipids metabolism pathway. S1P is significantly increased in the lesional skin . The TRPV4 channel was critical for S1P induced itch and pain. Sphingosine kinase 2 (SPHK2), the key enzyme controlling S1P synthesis, was significantly increased in lesional skin. ABC294640, a SPHK2 inhibitor, significantly decreased S1P concentration in lesional CD model skin, as well as in model associated epidermal hyperplasia and chronic pain and itch. In CD patients, SPHK2 expression and S1P concentration were significantly elevated compared to healthy control skin.
Conclusion and Implications: Our results indicate that, in CD, increased S1P induces chronic pain and itch partly through TRPV4. Inhibition of S1P synthesis or the S1P/S1P receptor-TRPV4 pathway are promising treatment strategies for CD associated pain and itch.
KEYWORDS
chronic dermatitis, itch, pain, S1P, TRPV4
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