Critical Role for Mast Cell Stat5 Activity in Skin Inflammation
Tomoaki Ando,
Wenbin Xiao,
Peisong Gao,
Siavash Namiranian,
Kenji Matsumoto,
Yoshiaki Tomimori,
Hong Hong,
Hirotaka Yamashita,
Miho Kimura,
Jun-ichi Kashiwakura,
Tissa R. Hata,
Kenji Izuhara,
Michael F. Gurish,
Axel Roers,
Nicholas M. Rafaels,
Kathleen C. Barnes,
Colin Jamora,
Yuko Kawakami,
Toshiaki Kawakami
Affiliations
Tomoaki Ando
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
Wenbin Xiao
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
Peisong Gao
Division of Allergy and Clinical Immunology, Johns Hopkins University, Baltimore, MD 21224, USA
Siavash Namiranian
Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
Kenji Matsumoto
Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan
Yoshiaki Tomimori
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
Hong Hong
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
Hirotaka Yamashita
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
Miho Kimura
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
Jun-ichi Kashiwakura
Laboratory for Allergic Disease, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Yokohama 230-0045, Japan
Tissa R. Hata
Division of Dermatology, Department of Medicine, University of California San Diego, La Jolla, CA 92037, USA
Kenji Izuhara
Division of Medical Biochemistry, Department of Biomolecular Sciences and Department of Laboratory Medicine, Saga Medical School, Saga 849-85-01, Japan
Michael F. Gurish
Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
Axel Roers
Institute for Immunology, University of Technology Dresden, Medical Faculty Carl-Gustav Carus, 01307 Dresden, Germany
Nicholas M. Rafaels
Division of Allergy and Clinical Immunology, Johns Hopkins University, Baltimore, MD 21224, USA
Kathleen C. Barnes
Division of Allergy and Clinical Immunology, Johns Hopkins University, Baltimore, MD 21224, USA
Colin Jamora
Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA
Yuko Kawakami
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
Toshiaki Kawakami
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
Atopic dermatitis (AD) is a chronic inflammatory skin disease. Here, we show that phospholipase C-β3 (PLC-β3)-deficient mice spontaneously develop AD-like skin lesions and more severe allergen-induced dermatitis than wild-type mice. Mast cells were required for both AD models and remarkably increased in the skin of Plcb3−/− mice because of the increased Stat5 and reduced SHP-1 activities. Mast cell-specific deletion of Stat5 gene ameliorated allergen-induced dermatitis, whereas that of Shp1 gene encoding Stat5-inactivating SHP-1 exacerbated it. PLC-β3 regulates the expression of periostin in fibroblasts and TSLP in keratinocytes, two proteins critically involved in AD pathogenesis. Furthermore, polymorphisms in PLCB3, SHP1, STAT5A, and STAT5B genes were associated with human AD. Mast cell expression of PLC-β3 was inversely correlated with that of phospho-STAT5, and increased mast cells with high levels of phospho-STAT5 were found in lesional skin of some AD patients. Therefore, STAT5 regulatory mechanisms in mast cells are important for AD pathogenesis.
