Foxo4-and Stat3-dependent IL-10 production by progranulin in regulatory T cells restrains inflammatory arthritis
Foxo4-and Stat3-dependent IL-10 production by progranulin in regulatory T cells restrains inflammatory arthritis
复制标题
DOI：
10.1096/fj.201601134r
复制
发表时间：
2017-04-01
期刊：
影响因子：
4.8
通讯作者：
Liu, Chuan-ju
中科院分区：
文献类型：
--
作者：
Fu, Wenyu;Hu, Wenhuo;Liu, Chuan-ju
颗粒蛋白前体（PGRN）抑制炎症，并对炎性关节炎有治疗作用;然而，其潜在的免疫学机制仍不清楚。在这项研究中，我们通过使用PGRN和IL-10基因修饰的小鼠模型，证明了PGN细胞因子IL-10是PGN介导的胶原诱导的关节炎抗炎的关键介质。IL-10绿色荧光蛋白免疫小鼠显示调节性T（Treg）细胞是响应PGRN的IL-10的主要来源。此外，PGRN介导的Treg细胞的扩增和活化以及IL-10的产生依赖于JNK信号传导，但不依赖于已知的PGRN活化的ERK和PI 3 K途径。此外，微阵列和染色质免疫沉淀测序筛选导致叉头盒蛋白O 4和信号转导子和转录激活子3的发现，作为（Treg）细胞中IL-10的PGRN诱导所需的转录因子。这些发现定义了一种以前未被认识到的信号通路，该通路是Treg细胞中PGRN产生IL-10的基础，并对PGRN解决炎症性疾病和自身免疫性疾病，特别是炎性关节炎中炎症的机制提出了新的见解。傅，W.，胡伟，Shi，L.，美国，Mundra，J. J. Xiao，G.，Dustin，M. L.，Liu，C.调节性T细胞中颗粒蛋白前体产生Foxo 4和Stat 3依赖性IL-10抑制炎症性关节炎
Progranulin (PGRN) restrains inflammation and is therapeutic against inflammatory arthritis; however, the underlying immunological mechanism remains unknown. In this study, we demonstrated that antiinflammatory cytokine IL-10 was a critical mediator for PGRN-mediated anti-inflammation in collagen-induced arthritisbyusingPGRNandIL-10geneticallymodifiedmousemodels. IL-10greenfluorescentproteinreportermice revealed that regulatory T (Treg) cells were the predominant source of IL-10 in response to PGRN. In addition, PGRN-mediated expansion and activation of Treg cells, as well as IL-10 production, depends on JNK signaling, but not on known PGRN-activated ERK and PI3K pathways. Furthermore, microarray and chromatin immunoprecipitation sequencing screens led to the discovery of forkhead box protein O4 and signal transducer and activator of transcription 3 as the transcription factors required for PGRNinduction of IL-10 in(Treg) cells. These findings define a previously unrecognized signaling pathway that underlies IL-10 production byPGRNin Treg cells and present new insights into the mechanisms by which PGRN resolves inflammation in inflammatory conditions and autoimmune diseases, particularly inflammatory arthritis.-Fu, W., Hu, W., Shi, L., Mundra, J. J. Xiao, G., Dustin, M. L., Liu, C. Foxo4-and Stat3-dependent IL-10 production by progranulin in regulatory T cells restrains inflammatory arthritis.