TY - JOUR
T1 - critical role for mast cell Stat5 activity in skin inflammation
AU - Ando, Tomoaki
AU - Xiao, Wenbin
AU - Gao, Peisong
AU - Namiranian, Siavash
AU - Matsumoto, Kenji
AU - Tomimori, Yoshiaki
AU - Hong, Hong
AU - Yamashita, Hirotaka
AU - Kimura, Miho
AU - Kashiwakura, Jun ichi
AU - Hata, Tissa R.
AU - Izuhara, Kenji
AU - Gurish, Michael F.
AU - Roers, Axel
AU - Rafaels, Nicholas M.
AU - Barnes, Kathleen C.
AU - Jamora, Colin
AU - Kawakami, Yuko
AU - Kawakami, Toshiaki
N1 - Funding Information:
We thank other ADVN members for allowing us to use the DNAs collected through the network. The ADVN was supported by the National Institute of Allergy and Infectious Diseases/NIH (N01 AI40030). We are thankful to Drs. Lothar Hennighausen, Klaus Rajewsky, and Steven F. Ziegler for donating mice. M.K. participated in this study as a graduate student in the Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine. This study was in part supported by contract and grants from the NIH (HHSN26620040033C), MPN Foundation, and Ministry of Education, Culture, Sports, Science and Technology of Japan. W.X. was supported in part by the Diabetes and Immune Disease National Research Institute, J.-i.K. was supported in part by the Takeda Science Foundation, and K.C.B. was supported in part by the Mary Beryl Patch Turnbull Scholar Program. This manuscript is Publication 1148 from the La Jolla Institute for Allergy and Immunology.
PY - 2014
Y1 - 2014
N2 - Atopic dermatitis (AD) is a chronic inflammatory skindisease. 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 withhuman AD. Mast cell expression of PLC-β3 was inversely correlated with that of phospho-STAT5, and increased mast cells with high levels ofphospho-STAT5 were found in lesional skin of some AD patients. Therefore, STAT5 regulatory mechanisms in mast cells are important for AD pathogenesis.
AB - Atopic dermatitis (AD) is a chronic inflammatory skindisease. 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 withhuman AD. Mast cell expression of PLC-β3 was inversely correlated with that of phospho-STAT5, and increased mast cells with high levels ofphospho-STAT5 were found in lesional skin of some AD patients. Therefore, STAT5 regulatory mechanisms in mast cells are important for AD pathogenesis.
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U2 - 10.1016/j.celrep.2013.12.029
DO - 10.1016/j.celrep.2013.12.029
M3 - Article
C2 - 24412367
AN - SCOPUS:84895910886
SN - 2211-1247
VL - 6
SP - 366
EP - 376
JO - Cell Reports
JF - Cell Reports
IS - 2
ER -