LPA Induces Keratinocyte Differentiation and Promotes Skin Barrier Function through the LPAR1/LPAR5-RHO-ROCK-SRF Axis

Akiko Sumitomo, Ratklao Siriwach, Dean Thumkeo, Kentaro Ito, Ryota Nakagawa, Nobuo Tanaka, Kohei Tanabe, Akira Watanabe, Mari Kishibe, Akemi Ishida-Yamamoto, Tetsuya Honda, Kenji Kabashima, Junken Aoki, Shuh Narumiya

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1010-1022
Number of pages13
JournalJournal of Investigative Dermatology
Volume139
Issue number5
DOIs
Publication statusPublished - 2019 May

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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