Tomoyuki Oshio1, Mayumi Komine2, Hidetoshi Tsuda3, Shin-Ichi Tominaga4, Hirohisa Saito5, Susumu Nakae6, Mamitaro Ohtsuki7. 1. Departments of Dermatology at Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Electronic address: kiyumoto-oshio@hotmail.co.jp. 2. Departments of Dermatology at Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan; Departments of Biochemistry at Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Electronic address: mkomine12@jichi.ac.jp. 3. Departments of Dermatology at Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Electronic address: thidet@jichi.ac.jp. 4. Departments of Biochemistry at Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Electronic address: shintomi@jichi.ac.jp. 5. Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. Electronic address: saito-hr@ncchd.go.jp. 6. Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Electronic address: snakae@ims.u-tokyo.ac.jp. 7. Departments of Dermatology at Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Electronic address: mamitaro@jichi.ac.jp.
Abstract
BACKGROUND: Skin is the outermost tissue of the human body, and works as a mechanical, chemical, and biological barrier. The epidermis is the uppermost layer of the skin, and keratinocytes constitute the majority of epidermal cells. Wounds are disruptions of skin integrity, and cause tremendous disadvantages to humans; accordingly, rapid wound healing is very important. Interleukin (IL)-33 is expressed in barrier tissue cells, such as epithelial and endothelial cells. Upon injury, IL-33 is released to stimulate immune cells, functioning as an "alarmin." ST2 is a receptor for IL-33; its soluble form (s)ST2 acts as a decoy receptor and competes for IL-33 binding. OBJECTIVES: We aimed to clarify the role of IL-33 in wound healing. MATERIALS AND METHODS: Wild-type (WT), IL-33 knockout (IL33 KO) mice, and sST2 transgenic (Tg) mice were wounded with a 4-mm punch, and the wound healing process was compared. Immunohistochemical analyses were performed to detect macrophages, neutrophils, and mast cells. Total RNA was extracted from the skin samples and real-time PCR was performed. An in vitro scratch wound assay was performed. RESULTS: Wound healing was delayed in IL33 KO mice compared to WT mice, while wound healing in sST2 Tg mice was comparable to that of WT mice. A histological examination showed delayed elongation of the epidermal tongue in IL-33 KO mice. An immunohistochemical study revealed prolonged neutrophilic infiltration at a later stage in IL-33 KO mice. IL-6, IL-1β, and CXCL1 transcripts were more abundant in the wounds of IL-33 KO mice than WT mice. Intraperitoneal administration of an NFκB inhibitor to IL-33 KO mice normalized the delayed wound healing and the enhanced expression of IL-6 in IL-33 KO mice. Epidermal keratinocytes from IL-33 KO mice showed delayed wound closure compared to those from WT mice. CONCLUSION: Our results indicate that nuclear IL-33, but not IL-33 as a cytokine, has beneficial effects on wound healing in mice, probably by suppressing NFκB to inhibit excessive inflammation and by maintaining keratinocyte proliferation or migration for epithelialization.
BACKGROUND: Skin is the outermost tissue of the human body, and works as a mechanical, chemical, and biological barrier. The epidermis is the uppermost layer of the skin, and keratinocytes constitute the majority of epidermal cells. Wounds are disruptions of skin integrity, and cause tremendous disadvantages to humans; accordingly, rapid wound healing is very important. Interleukin (IL)-33 is expressed in barrier tissue cells, such as epithelial and endothelial cells. Upon injury, IL-33 is released to stimulate immune cells, functioning as an "alarmin." ST2 is a receptor for IL-33; its soluble form (s)ST2 acts as a decoy receptor and competes for IL-33 binding. OBJECTIVES: We aimed to clarify the role of IL-33 in wound healing. MATERIALS AND METHODS: Wild-type (WT), IL-33 knockout (IL33 KO) mice, and sST2 transgenic (Tg) mice were wounded with a 4-mm punch, and the wound healing process was compared. Immunohistochemical analyses were performed to detect macrophages, neutrophils, and mast cells. Total RNA was extracted from the skin samples and real-time PCR was performed. An in vitro scratch wound assay was performed. RESULTS: Wound healing was delayed in IL33 KO mice compared to WT mice, while wound healing in sST2 Tg mice was comparable to that of WT mice. A histological examination showed delayed elongation of the epidermal tongue in IL-33 KO mice. An immunohistochemical study revealed prolonged neutrophilic infiltration at a later stage in IL-33 KO mice. IL-6, IL-1β, and CXCL1 transcripts were more abundant in the wounds of IL-33 KO mice than WT mice. Intraperitoneal administration of an NFκB inhibitor to IL-33 KO mice normalized the delayed wound healing and the enhanced expression of IL-6 in IL-33 KO mice. Epidermal keratinocytes from IL-33 KO mice showed delayed wound closure compared to those from WT mice. CONCLUSION: Our results indicate that nuclear IL-33, but not IL-33 as a cytokine, has beneficial effects on wound healing in mice, probably by suppressing NFκB to inhibit excessive inflammation and by maintaining keratinocyte proliferation or migration for epithelialization.
Authors: Sonia C DaSilva-Arnold; Anita Thyagarajan; Leroy J Seymour; Qiaofang Yi; Joshua R Bradish; Mohammed Al-Hassani; Hongming Zhou; Nikolajs J Perdue; Val Nemeth; Aleksandar Krbanjevic; Ana P M Serezani; Matthew R Olson; Dan F Spandau; Jeffrey B Travers; Mark H Kaplan; Matthew J Turner Journal: Arch Dermatol Res Date: 2018-01-24 Impact factor: 3.017
Authors: Andrew Clerman; Zahid Noor; Rita Fishelevich; Virginia Lockatell; Brian S Hampton; Nirav G Shah; Mariah V Salcedo; Nevins W Todd; Sergei P Atamas; Irina G Luzina Journal: J Biol Chem Date: 2017-11-10 Impact factor: 5.157
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