Phospholipase Cδ 1 regulates p38 MAPK activity and skin barrier integrity

Kaori Kanemaru, Yoshikazu Nakamura, Kengo Totoki, Takatsugu Fukuyama, Madoka Shoji, Hisae Kaneko, Kanako Shiratori, Atsuko Yoneda, Takafumi Inoue, Yoichiro Iwakura, Kenji Kabashima, Kiyoko Fukami

    Research output: Contribution to journalArticle

    11 Citations (Scopus)

    Abstract

    Keratinocytes undergo a unique type of programmed cell death known as cornification, which leads to the formation of the stratum corneum (SC), the main physical barrier of the epidermis. A defective epidermal barrier is a hallmark of the two most common inflammatory skin disorders, psoriasis, and atopic dermatitis. However, the detailed molecular mechanisms of skin barrier formation are not yet fully understood. Here, we showed that downregulation of phospholipase C (PLC) d 1, a Ca 2+-mobilizing and phosphoinositide-metabolizing enzyme abundantly expressed in the epidermis, impairs the barrier functions of the SC. PLCd 1 downregulation also impairs localization of tight junction proteins. Loss of PLCd 1 leads to a decrease in intracellular Ca 2+ concentrations and nuclear factor of activated T cells activity, along with hyperactivation of p38 mitogen-activated protein kinase (MAPK) and inactivation of RhoA. Treatment with a p38 MAPK inhibitor reverses the barrier defects caused by PLCd 1 downregulation. Interestingly, this treatment also attenuates psoriasis-like skin inflammation in imiquimod-treated mice. These findings demonstrate that PLCd 1 is essential for epidermal barrier integrity. This study also suggests a possible link between PLCd 1 downregulation, p38 MAPK hyperactivation, and barrier defects in psoriasis-like skin inflammation.

    Original languageEnglish
    Pages (from-to)1079-1090
    Number of pages12
    JournalCell Death and Differentiation
    Volume24
    Issue number6
    DOIs
    Publication statusPublished - 2017 Jun 1

      Fingerprint

    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

    Cite this

    Kanemaru, K., Nakamura, Y., Totoki, K., Fukuyama, T., Shoji, M., Kaneko, H., Shiratori, K., Yoneda, A., Inoue, T., Iwakura, Y., Kabashima, K., & Fukami, K. (2017). Phospholipase Cδ 1 regulates p38 MAPK activity and skin barrier integrity. Cell Death and Differentiation, 24(6), 1079-1090. https://doi.org/10.1038/cdd.2017.56