Sphingosine 1-phosphate receptor 1 and 5 paradoxically regulate IL-9 and IL-13 production in atopic dermatitis

Summary: Abstract Body: Atopic dermatitis (AD) is a common inflammatory skin disease associated with TH2, TH9, and TH22 skewing. Recent studies have identified that various lipid mediators are associated with TH skewing. However, the relationship between the TH skewing in AD and those lipid mediators is not fully understood. In this study, we sought to determine the lipid mediator that impacts cytokine production in AD-related TH skewing. RNA-sequencing carried out in CD3+/– T cells from AD patients showed significant changes of several lipid mediator-related genes including sphingosine 1-phosphate receptor (S1PR) 5, which is one of the receptor subtypes in S1PRs. Indeed, serum S1P levels were increased in AD patients and intracellular staining using PBMCs showed that S1P treatment enhanced IL-13 and IL-9 production from CD4+ T cells. Our further results indicate that the S1P signal paradoxically regulates IL-13 and IL-9 production through S1PR5 and S1PR1. This is the most comprehensive profiling of bioactive lipid mediators, which impact TH skewing, as well as the first study to evaluate the role of S1P-S1PR1/S1PR5 signaling in AD. Our results suggest that S1PR5 and S1PR1 may be therapeutic targets for controlling IL-13/IL-9-associated immunoinflammatory responses in AD. Kazuhiko Yamamura^{1, 2}, Sandra Garcet³, Juana Gonzalez³, Shunsuke Miura⁴, Mika Murai-Yamamura¹, Xuan Li³, Yael Renert-Yuval³, Takeshi Nakahara^{1, 2}, James Krueger³, Emma Guttman-Yassky⁵ 1. Dermatology, Kyushu University, Fukuoka, Fukuoka, Japan. 2. Research and Clinical Center for Yusho and Dioxin, Fukuoka, Fukuoka, Japan. 3. Laboratory of Investigative Dermatology, The Rockefeller University, New York, NY, United States. 4. Dermatology, Tokyo University, Tokyo, Japan. 5. Dermatology, Icahn School of Medicine at the Mount Sinai Medical Center, New York, NY, United States. Translational Studies: Cell and Molecular Biology