Skin harbors several barriers to prevent easy penetration of external antigens 47barriers form and are maintained are largely unknown.into the body. However, the exact molecular mechanisms by which the skin Epidermis, the outermost component of the skin, is composed of keratino-cytes and consists of the stratum basale, stratum spinosum, stratum granulo-sum (SG), and stratum corneum (SC), from bottom to top. Our group has been focusing on the SC as an air-liquid barrier and the tight junction as a liquid-liq-uid barrier formed between SG2 cells, among many other skin barriers. There is a fundamental biophysical paradox regarding the function of the epidermis, how it can maintain the barrier, yet still constantly replace and shed cells.Our group is trying to clarify how epidermal barrier homeostasis is main-tained under normal conditions and how impaired barrier function occurs and affects microenvironments of the skin in various disease conditions. Our experimental approaches are comprehensive, combining molecular biology, biochemistry, ultrastructural anatomy, live imaging, microbiology, and systems biology. We show via intravital imaging of mouse skin that SG1 cell death is preceded by prolonged (~60 min) intracellular Ca2+ elevation (phase I) and rapid intracellular acidification (phase II). These findings provide an important framework to understand the unique cell death pathway in keratinocytes, which we termed ‘corneoptosis’.Another of our strengths is to be able to go back and forth between our basic science findings in mice and those in clinical science in humans with various skin diseases. Based on the discovery of corneoptosis, we are now examining how corneoptosis and pH regulation in SC are impaired in the presence of in-flammation, such as in atopic dermatitis. Our goal is to understand skin barrier homeostasis in health and disease and to provide more targeted therapeutic approaches with fewer side effects to patients suffering from inflammatory skin diseases.Figure: Comprehensive analysis of skin barrier homeostasisOur team is working to clarify the mechanisms of skin barrier homeostasis by focusing on the stratum corneum (SC), tight junction (TJ) and SG1 cells. We established a live imaging system, especially focusing on a unique type of SG1 cell death termed ‘corneoptosis’ and pH changes in the SC. We found that corneoptosis is composed of two phases (phase I and II) by using an optimized plasmid injection method to study the corni-fication process in mice. We also found that SC has three stepwise pH zones and we are currently studying the host-microbe interactions on skin and intracellular pH in inflammatory skin conditions.Recent Major PublicationsTakahashi H, Nomura H, Iriki H, Kubo A, Isami K, Mikami Y, Mukai M, Sasaki T, Yamagami J, Kudo J, Ito H, Kamata A, Kurebayashi Y, Yoshida H, Yoshimura A, Sun H, Sue-matsu M, O’Shea JJ, Kanno Y, and Amagai M. Cholesterol 25-hydroxylase is a metabolic switch to constrain T cell-mediated inflammation in the skin. Sci Immunol 6, eabb6444 (2021)Matsui T, Kadono-Maekubo N, Suzuki Y, Furuichi Y, Shi-raga K, Sasaki H, Ishida A, Takahashi S, Okada T, Toyooka K, Sharif J, Abe T, Kiyonari H, Tominaga M, Miyawaki A, Amagai M. A unique mode of keratinocyte death requires intracellular acidification. Proc Natl Acad Sci U S A 118, e2020722118 (2021)Ito Y, Sasaki T, Li Y, Tanoue T, Sugiura Y, Skelly AN, Suda W, Kawashima Y, Okahashi N, Watanabe E, Horikawa H, Shiohama A, Kurokawa R, Kawakami E, Iseki H, Kawasaki H, Iwakura Y, Shiota A, Yu L, Hisatsune J, Koseki H, Sugai M, Arita M, Ohara O, Matsui T, Suematsu M, Hattori M, Atarashi K, Amagai M, Honda K. Staphylococcus cohnii is a potentially biotherapeutic skin commensal alleviating skin inflammation. Cell Rep 35, 109052 (2021)Invited presentationsAmagai M. “Corneoptosis, functional cell death of kera-tinocytes” SLDDDRS Webinar Series 2021-2023, Stanford University (Online) November 2021Amagai M. “Corneoptosis, unique cell death process of keratinocytes” The 18th International Symposium of the Cutaneous Biology Research Institute, Yonsei University College of Medicine (Online) October 2021Amagai M. “Peripheral tolerance to desmoglein3, pem-phigus vulgaris antigen” 2021 Annual Scientific Meeting of Australasian Society for Dermatological Research (Online) July 2021Amagai M. “Corneoptosis, unique cell death process of keratinocyte” ISBS 2021 World Congress on Biophysics and Imaging of the Skin, hybrid (Berlin, Germany/On-line) June 2021Amagai M. “Chasing after simple logic behind a complex disease, pemphigus” Aaron Lerner Discovery Lecture 2021, Yale University (Online) April 2021Laboratory for Skin HomeostasisTeam Leader: Masayuki Amagai
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