Skin is the place where immunity meets external antigens. Cutaneous sen-44sitization is now considered to be the initial key step in many allergic dis-orders, not only atopic dermatitis (AD), but also asthma, food allergy, and ana-phylaxis. Skin harbors several barriers to prevent easy penetration of external antigens into the body. However, the exact molecular mechanisms by which the skin barriers form and are maintained are largely unknown.Epidermis, the outermost component of the skin, is composed of keratin-ized stratified squamous epithelia and consists of the stratum basale, stratum spinosum, stratum granulosum (SG) and stratum corneum (SC), from bottom to top (Figure). Our group has been focusing on the SC as an air-liquid barrier and the tight junction (TJ) as a liquid-liquid barrier formed between SG2 cells, among many other skin barriers. There is a fundamental biophysical paradox regarding the function of the epidermis, namely, how it can maintain the bar-rier, yet still constantly replace and shed cells.Our group is trying to clarify how epidermal barrier homeostasis in 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 be-gins with an irreversible sustained elevation of intracellular Ca2+, followed by rapid acidification. We demonstrate via intravital imaging procedures that SG1 cells die after prolonged (~60 min) intracellular Ca2+ elevation (phase I). Next, irreversibly sustained rapid intracellular acidification is induced (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. Our goal is to understand skin barrier homeostasis in health and disease and to provide more targeted therapeutic approaches with fewer side ef-fects to patients suffering from severe allergic diseases.Figure: Comprehensive analysis of skin barrier homeostasisOur team is trying to clarify the mechanisms of skin bar-rier 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 SG1 cell death pathway termed ‘corneoptosis’. By using an optimized plasmid injection method to study the cor-nification process in mice, we found that corneoptosis occurs in two sequential phases (phase I and II). We also study host-microbe interactions on skin.Recent Major PublicationsMatsui 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)Atsugi T, Yokouchi M, Hirano T, Hirabayashi A, Nagai T, Ohyama M, Abe T, Kaneko M, Zouboulis CC, Amagai M, Kubo A. Holocrine Secretion Occurs outside the Tight Junction Barrier in Multicellular Glands: Lessons from Claudin-1-Deficient Mice. J Invest Dermatol 140, 298-308. e5 (2020)Someya T, Amagai M. Toward a new generation of smart skins. Nat Biotechnol 37, 382-388 (2019)Invited presentationsAmagai M. “Cracking the codes of autoimmune disease, pemphigus.” the 46th annual meeting of Taiwanese Dermatological Association (Kaohsiung, Taiwan/Online) November 2020Amagai M. “Solving skin barrier homeostatic mecha-nisms by in vivo imaging.” UCSF Dermatology Grand Rounds (San Francisco, USA/Online) November 2020Amagai M. “Homeostatic mechanisms of skin barrier and their disruption in skin inflammation.” JSA/WAO Joint Congress 2020 (Kyoto/Online) September 2020Laboratory for Skin HomeostasisTeam Leader: Masayuki Amagai
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