TY - JOUR
T1 - LPA Induces Keratinocyte Differentiation and Promotes Skin Barrier Function through the LPAR1/LPAR5-RHO-ROCK-SRF Axis
AU - Sumitomo, Akiko
AU - Siriwach, Ratklao
AU - Thumkeo, Dean
AU - Ito, Kentaro
AU - Nakagawa, Ryota
AU - Tanaka, Nobuo
AU - Tanabe, Kohei
AU - Watanabe, Akira
AU - Kishibe, Mari
AU - Ishida-Yamamoto, Akemi
AU - Honda, Tetsuya
AU - Kabashima, Kenji
AU - Aoki, Junken
AU - Narumiya, Shuh
N1 - Funding Information:
DT and SN were supported by the Coordination Fund from JST and Astellas Pharma Inc. SN is a scientific advisor to Astellas Pharma Inc. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
We thank J. Monypenny for critical reading of the manuscript; K. Kano and T. Dainichi for technical advice; N. Asamoto and K. Naruo for technical assistance; and A. Washimi, T. Arai, Y. Nakanishi, and T. Ijiri for their secretarial assistance. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan , Japan (DT, SN); by a research grant from Ono Medical Research Foundation , Japan (DT); and by the Special Coordination Funds by the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan; and Astellas Pharma Inc. in Creation of Innovation Centers for Advanced Interdisciplinary Research Areas, Japan (DT, SN).
Publisher Copyright:
© 2018 The Authors
PY - 2019/5
Y1 - 2019/5
N2 - The skin barrier protects the body from water loss, allergens, and pathogens. Profilaggrin is produced by differentiated keratinocytes and is processed into filaggrin monomers. These monomers cross-link keratin filaments and are also decomposed to natural moisturizing factors in the stratum corneum for skin hydration and barrier function. Deficits in FLG expression impair skin barrier function and underlie skin diseases such as dry skin and atopic dermatitis. However, intrinsic factors that regulate FLG expression and their mechanisms of action remain unknown. Here, we show that lysophosphatidic acid induces FLG expression in human keratinocytes via the LPAR1 and LPAR5 receptors and the downstream RHO-ROCK-SRF pathway. Comprehensive gene profiling analysis further showed that lysophosphatidic acid not only induces FLG expression but also facilitates keratinocyte differentiation. Moreover, lysophosphatidic acid treatment significantly up-regulated FLG production in a three-dimensional culture model of human skin and promoted barrier function in mouse skin in vivo. Thus, our work shows a previously unsuspected role for lysophosphatidic acid and its downstream signaling in the maintenance of skin homeostasis, which may serve as a novel therapeutic target for skin barrier dysfunction.
AB - The skin barrier protects the body from water loss, allergens, and pathogens. Profilaggrin is produced by differentiated keratinocytes and is processed into filaggrin monomers. These monomers cross-link keratin filaments and are also decomposed to natural moisturizing factors in the stratum corneum for skin hydration and barrier function. Deficits in FLG expression impair skin barrier function and underlie skin diseases such as dry skin and atopic dermatitis. However, intrinsic factors that regulate FLG expression and their mechanisms of action remain unknown. Here, we show that lysophosphatidic acid induces FLG expression in human keratinocytes via the LPAR1 and LPAR5 receptors and the downstream RHO-ROCK-SRF pathway. Comprehensive gene profiling analysis further showed that lysophosphatidic acid not only induces FLG expression but also facilitates keratinocyte differentiation. Moreover, lysophosphatidic acid treatment significantly up-regulated FLG production in a three-dimensional culture model of human skin and promoted barrier function in mouse skin in vivo. Thus, our work shows a previously unsuspected role for lysophosphatidic acid and its downstream signaling in the maintenance of skin homeostasis, which may serve as a novel therapeutic target for skin barrier dysfunction.
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U2 - 10.1016/j.jid.2018.10.034
DO - 10.1016/j.jid.2018.10.034
M3 - Article
C2 - 30447238
AN - SCOPUS:85060765675
VL - 139
SP - 1010
EP - 1022
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
SN - 0022-202X
IS - 5
ER -