PMID- 29535261 OWN - NLM STAT- MEDLINE DCOM- 20190916 LR - 20190916 IS - 1937-9145 (Electronic) IS - 1945-0877 (Linking) VI - 11 IP - 521 DP - 2018 Mar 13 TI - p38alpha signaling in Langerhans cells promotes the development of IL-17-producing T cells and psoriasiform skin inflammation. LID - eaao1685 [pii] LID - 10.1126/scisignal.aao1685 [doi] AB - Dendritic cells (DCs) contribute to psoriasis pathogenesis. In a mouse model of imiquimod-induced psoriasiform skin inflammation, we found that p38alpha activity in Langerhans cells (LCs), a skin-resident subset of DCs, promoted the generation of T cells that produce IL-17, a proinflammatory cytokine that is implicated in autoimmune disease. Deletion of p38alpha in LCs, but not in other skin or circulating DC subsets or T cells, decreased T cell-mediated psoriasiform skin inflammation in mice. The activity of p38alpha in LCs specifically promoted IL-17 production from gammadelta and CD4(+) T cells by increasing the abundance of IL-23 and IL-6, two cytokines that stimulate IL-17 secretion. Inhibition of p38 activity through either pharmacological inhibition or genetic deletion also reduced the severity of established psoriasiform skin inflammation. Together, our findings indicate a critical role for p38alpha signaling in LCs in promoting inflammatory responses in the skin and suggest that targeting p38alpha signaling in LCs may offer an effective therapeutic approach to treat psoriasis. CI - Copyright (c) 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. FAU - Zheng, Tingting AU - Zheng T AUID- ORCID: 0000-0001-9147-2115 AD - Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Institute of Immunology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. FAU - Zhao, Weiheng AU - Zhao W AUID- ORCID: 0000-0002-5726-6892 AD - Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Institute of Immunology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. FAU - Li, Hongjin AU - Li H AUID- ORCID: 0000-0002-4408-9612 AD - Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Institute of Immunology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. FAU - Xiao, Shuxiu AU - Xiao S AD - Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Institute of Immunology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. FAU - Hu, Ran AU - Hu R AD - Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Institute of Immunology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. FAU - Han, Miaomiao AU - Han M AD - Xin Hua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China. FAU - Liu, Heng AU - Liu H AD - Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, China. FAU - Liu, Yeqiang AU - Liu Y AD - Shanghai Skin Disease Hospital, Tongji University, Shanghai 200443, China. FAU - Otsu, Kinya AU - Otsu K AUID- ORCID: 0000-0001-9697-0711 AD - Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan. AD - Cardiovascular Division, King's College London, London WC2R 2LS, UK. FAU - Liu, Xinguang AU - Liu X AD - Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, China. FAU - Huang, Gonghua AU - Huang G AUID- ORCID: 0000-0003-1579-5478 AD - Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Shanghai Institute of Immunology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. gonghua.huang@shsmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180313 PL - United States TA - Sci Signal JT - Science signaling JID - 101465400 RN - 0 (Imidazoles) RN - 0 (Interleukin-17) RN - 0 (Interleukin-23) RN - 0 (Interleukin-6) RN - 0 (Pyridines) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 14) RN - OU13V1EYWQ (SB 203580) RN - P1QW714R7M (Imiquimod) SB - IM MH - Animals MH - Cells, Cultured MH - Dendritic Cells/immunology MH - Disease Models, Animal MH - Imidazoles/pharmacology MH - Imiquimod MH - Inflammation/immunology/metabolism MH - Interleukin-17/immunology/metabolism MH - Interleukin-23/immunology/metabolism MH - Interleukin-6/immunology/metabolism MH - Langerhans Cells/*immunology/metabolism MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Mitogen-Activated Protein Kinase 14/antagonists & inhibitors/*immunology/metabolism MH - Psoriasis/chemically induced/*immunology/metabolism MH - Pyridines/pharmacology MH - Signal Transduction/drug effects/*immunology MH - Skin/immunology/metabolism/pathology MH - T-Lymphocytes/*immunology/metabolism MH - Th17 Cells/*immunology/metabolism EDAT- 2018/03/15 06:00 MHDA- 2019/09/17 06:00 CRDT- 2018/03/15 06:00 PHST- 2018/03/15 06:00 [entrez] PHST- 2018/03/15 06:00 [pubmed] PHST- 2019/09/17 06:00 [medline] AID - 11/521/eaao1685 [pii] AID - 10.1126/scisignal.aao1685 [doi] PST - epublish SO - Sci Signal. 2018 Mar 13;11(521):eaao1685. doi: 10.1126/scisignal.aao1685.