Lysophosphatidic acid facilitates human keratinocyte differentiation through the LPAR1/LPAR5-Rho-ROCK-SRF axis and promotes skin barrier function

[Speaker] Kohei Tanabe:1
[Co-author] Ratklao Siriwach:1,2, Akiko Sumitomo:2, Kentaro Ito:2, Dean Thumkeo:1,2, Junken Aoki:3, Shuh Narumiya:1,2
1:Drug Discovery Medicine, Graduate School of Medicine, Kyoto University, Japan, 2:Center of Innovation in Immunoregulation Technology and Therapeutics, Kyoto University, Japan, 3:Graduate School of Pharmaceutical Sciences, Tohoku University, Japan

 Skin barrier is important for the moisture maintenance and function of our skin. One of the most important gene that constitutes our skin barrier is filaggrin (FLG). Deficits in FLG expression results in skin barrier dysfunction and causes atopic dermatitis (AD). To elucidate molecular mechanism maintaining skin barrier, we sought to identify factors that could enhance FLG gene expression in human keratinocytes, and evaluate the effect of such factors under physiological condition.
 We first identified G-protein coupled receptors (GPCRs) highly expressed in normal human epidermal keratinocytes (NHEKs) using GPCR array and next examined effects of agonists of these GPCRs on FLG expression by qRT-PCR and Western blot. We then validated GPCRs mediating the above effects on FLG gene expression, using selective agonists/antagonists and small interfering RNA (siRNA). We further conducted comprehensive analysis of gene expression induced by their activation, and identified signaling pathway leading to this induction by using pharmacological inhibitors. Finally, we tested the potential of this pathway for promoting skin barrier function under physiological condition by applying an agonist of the identified GPCRs to the 3D culture of human skin and experimental mice.
 In summary, we identified that lysophosphatidic acid (LPA) could induce keratinocyte differentiation in NHEKs. LPA signals through LPAR1 and LPAR5 and then activate Rho-ROCK-SRF signaling pathway indispensable for expression of variety of skin barrier genes including FLG. Moreover, we demonstrated that LPA treatment significantly promoted skin barrier function in vivo. Therefore, LPAR1 and LPAR5 signaling may serve as a new therapeutic target for diseases associated with skin barrier dysfunction such as AD.

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