T cell-derived iNOS switches off TH17 cell differentiation in inflammation

T 细胞衍生的 iNOS 在炎症中关闭 TH17 细胞分化

基本信息

  • 批准号:
    9116764
  • 负责人:
  • 金额:
    $ 42.38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-09-01 至 2018-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Although it has been demonstrated that iNOS plays an important role in host defense against microbial pathogens, the exact function of iNOS in T cells and chronic inflammatory diseases has not been defined. TH17 cells, which secrete interleukin 17 (IL-17) and IL-22 comprise a recently identified subset of CD4+ T cells distinct from the TH1 and TH2 subsets and RORgt has been identified as a key transcription factor for TH17 cell differentiation. Increasing evidence indicates that TH17 immune responses are involved in the pathogenesis of various autoimmune/inflammatory diseases. Thus, blocking TH17 cell activation could lead to the development of novel strategies for the treatment of chronic inflammatory diseases. We show that iNOS knock out mice display more robust TH17 cell differentiation without major effects on either TH1 or TH2 cell lineages. We demonstrated that iNOS protein was induced in activated CD4+ T cells and the use of an iNOS selective inhibitor L-NIL significantly increased the percentage of IL-17-producing CD4+ T cells in WT cell cultures, while, an NO donor, SNAP, dose-dependently suppressed IL-17 production in WT and iNOS-/- T cell cultures. In addition, tyrosine residues of RORgt protein were nitrated resulting in the inhibition of RORgt-mediated IL-17 promoter activation. Finally, transfer of iNOS-/- CD4+CD45Rbhi cells into RAG-/- mice induces more severe colitis compared to control CD4+CD45Rbhi cells and mice reconstituted with iNOS-/- cells had a significantly higher percentage of IL-17-producing cells than control mice. The results suggest that T cell-derived iNOS negatively regulates the development of TH17 immune responses resulting in the control of inflammation. This proposal is structured around three aims: 1) We will characterize the molecular mechanisms involved in the regulation of TH17 cell differentiation by T cell-derived iNOS. 2) We will characterize the function of T cell- derived-iNOS on human TH17, TH1, TH2, and Treg cell development. 3) We will analyze the roles of iNOS in different cell compartments including macrophages, dendritic cells, and T cells in the development of colitis. The proposed studies will define a novel transcriptional inhibitor of TH17 cell differentiation and highlight th importance of T cell-derived iNOS as a novel therapeutic target for the treatment of chronic inflammatory diseases.
描述(由申请人提供):虽然已经证明iNOS在宿主防御微生物病原体中起重要作用,但iNOS在T细胞和慢性炎性疾病中的确切功能尚未确定。分泌白细胞介素17(IL-17)和IL-22的TH 17细胞包含最近鉴定的不同于TH 1和TH 2亚群的CD 4 + T细胞亚群,并且RORgt已被鉴定为TH 17细胞分化的关键转录因子。越来越多的证据表明,TH 17免疫应答参与各种自身免疫/炎性疾病的发病机制。因此,阻断TH 17细胞活化可能会导致治疗慢性炎症性疾病的新策略的发展。我们发现,iNOS敲除小鼠显示出更强大的TH 17细胞分化,而对TH 1或TH 2细胞谱系没有重大影响。我们证明了iNOS蛋白在活化的CD 4 + T细胞中被诱导,并且iNOS选择性抑制剂L-NIL的使用显著增加了WT细胞培养物中产生IL-17的CD 4 + T细胞的百分比,而NO供体SNAP剂量依赖性地抑制WT和iNOS-/- T细胞培养物中IL-17的产生。此外,RORgt蛋白的酪氨酸残基被硝化, 抑制RORgt介导的IL-17启动子活化。最后,与对照CD 4 + CD 45 Rbhi细胞相比,将iNOS-/-CD 4 + CD 45 Rbhi细胞转移到RAG-/-小鼠中诱导更严重的结肠炎,并且用iNOS-/-细胞重建的小鼠比对照小鼠具有显著更高百分比的IL-17产生细胞。结果表明,T细胞衍生的iNOS负调节TH 17免疫应答的发展,导致炎症的控制。本研究的主要目的是:1)研究T细胞诱导型一氧化氮合酶(iNOS)对TH 17细胞分化的调控机制。2)我们将表征T细胞衍生的iNOS对人TH 17、TH 1、TH 2和Treg细胞发育的功能。3)我们将分析iNOS在不同细胞区室中的作用,包括巨噬细胞,树突状细胞和T细胞在结肠炎的发展中。这些研究将确定一种新的TH 17细胞分化的转录抑制剂,并强调T细胞衍生的iNOS作为治疗慢性炎症性疾病的新靶点的重要性。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Reprogramming macrophage orientation by microRNA 146b targeting transcription factor IRF5.
  • DOI:
    10.1016/j.ebiom.2016.10.041
  • 发表时间:
    2016-12
  • 期刊:
  • 影响因子:
    11.1
  • 作者:
    Peng, Liang;Zhang, Hui;Hao, Yuanyuan;Xu, Feihong;Yang, Jianjun;Zhang, Ruihua;Lu, Geming;Zheng, Zihan;Cui, Miao;Qi, Chen-Feng;Chen, Chun;Wang, Juan;Hu, Yuan;Wang, Di;Pierce, Susan;Li, Liwu;Xiong, Huabao
  • 通讯作者:
    Xiong, Huabao
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HUABAO XIONG其他文献

HUABAO XIONG的其他文献

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{{ truncateString('HUABAO XIONG', 18)}}的其他基金

T cell-derived iNOS switches off TH17 cell differentiation in inflammation
T 细胞衍生的 iNOS 在炎症中关闭 TH17 细胞分化
  • 批准号:
    8474949
  • 财政年份:
    2013
  • 资助金额:
    $ 42.38万
  • 项目类别:
T cell-derived iNOS switches off TH17 cell differentiation in inflammation
T 细胞衍生的 iNOS 在炎症中关闭 TH17 细胞分化
  • 批准号:
    8722431
  • 财政年份:
    2013
  • 资助金额:
    $ 42.38万
  • 项目类别:
Silencing of Th17 cell differentiation by IRF8 in the development of colitis
IRF8 在结肠炎发展过程中沉默 Th17 细胞分化
  • 批准号:
    8305224
  • 财政年份:
    2011
  • 资助金额:
    $ 42.38万
  • 项目类别:
THE ROLE OF ICSBP IN MUCOSAL IMMUNE RESPONSE
ICSBP 在粘膜免疫反应中的作用
  • 批准号:
    7484982
  • 财政年份:
    2007
  • 资助金额:
    $ 42.38万
  • 项目类别:
THE ROLE OF ICSBP IN MUCOSAL IMMUNE RESPONSE
ICSBP 在粘膜免疫反应中的作用
  • 批准号:
    7141824
  • 财政年份:
    2006
  • 资助金额:
    $ 42.38万
  • 项目类别:
THE ROLE OF ICSBP IN MUCOSAL IMMUNE RESPONSE
ICSBP 在粘膜免疫反应中的作用
  • 批准号:
    8136665
  • 财政年份:
  • 资助金额:
    $ 42.38万
  • 项目类别:
THE ROLE OF ICSBP IN MUCOSAL IMMUNE RESPONSE
ICSBP 在粘膜免疫反应中的作用
  • 批准号:
    7683157
  • 财政年份:
  • 资助金额:
    $ 42.38万
  • 项目类别:
THE ROLE OF ICSBP IN MUCOSAL IMMUNE RESPONSE
ICSBP 在粘膜免疫反应中的作用
  • 批准号:
    7921633
  • 财政年份:
  • 资助金额:
    $ 42.38万
  • 项目类别:

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