Effect of Bacterial Tolerance on TLR4 Signal Transduction

细菌耐受性对 TLR4 信号转导的影响

基本信息

项目摘要

DESCRIPTION (provided by applicant): Sepsis is a major threat to human health in the US, affecting ~750,000 Americans per year, with an associated mortality rate >28%. Many septic patients develop profound immunosuppression manifested by decreased production of pro-inflammatory cytokines and chemokines. This is highly reminiscent of endotoxin tolerance, a state of re-programming of TLR4 responses after a prior exposure to LPS. Endotoxin tolerance can be used as a model to delineate mechanisms that underlie altered monocyte responses in patients with sepsis. During the period of funding, we have identified new hallmarks of endotoxin tolerance. These include: (i) deficient tyrosine phosphorylation of TLR4 and adapter protein Mal; (ii) suppressed LPS-induced signalosome assembly amongst TLR4, adapter protein TRIF and kinase TBK1; (iii) deficient activation of TBK1 and transcription factor IRF-3; and (iv) increased expression of negative regulators Tollip, IRAK-M, SHIP-1, SOCS-1, SARM, and SIKE. Our preliminary data in THP1 cells and human monocytes show decreased LPS- induced c-Src and Lyn phosphorylation and Lyn-TLR4 interactions; inhibited activation of kinases IRAK4 and TAK-1; impaired K63-linked polyubiquitination of IRAK1 and TRAF-6; suppressed interactions of ubiquitinated IRAK1 with TRAF6 and IKK3; and increased expression of A20, a key deubiquitinating enzyme. Furthermore, we found reduced LPS tolerance induction upon inhibition of protein tyrosine phosphatases or by A20 gene knockdown, indicating a crucial role for altered tyrosine phosphorylation and K63-linked polyubiquitination in tolerance. Based on these data, we hypothesize that LPS tolerance alters post-translational modifications of TLR4, Mal and IRAK kinases and increases levels of negative regulators of TLR signaling, leading to reprogramming of TLR responses through changes in proximal signalosome compositions. This hypothesis will be tested in the following Specific Aims: 1. Identify kinases and phosphatases involved in phosphorylation of TLR4 and Mal and determine the impact of LPS tolerance on their expression and activities; 2. Define mechanisms by which LPS tolerance alters signalosome assembly and activation of proximal adapter-kinase modules; and 3. Elucidate molecular basis of interference in TLR4 signaling by negative regulatory molecules associated with LPS tolerance. These studies will determine new mechanisms responsible for tolerance and identify key intermediates affected. They will lay the groundwork for our future research in animal models of sepsis in vivo and translational studies in septic patients, with the goal of facilitating development of new therapeutic strategies to improve treatments for septic patients. These advances would be of key importance for improving public health in septic patients in the U.S.
描述(由申请人提供):败血症是美国人类健康的主要威胁,每年影响约75万美国人,相关死亡率约为28%。许多脓毒症患者出现严重的免疫抑制,表现为促炎细胞因子和趋化因子的产生减少。这很容易让人联想到内毒素耐受性,即在先前暴露于LPS后TLR4反应的重新编程状态。内毒素耐受性可以作为模型来描述脓毒症患者单核细胞反应改变的机制。在资助期间,我们已经确定了内毒素耐受性的新标志。这些包括:(i) TLR4和适配蛋白Mal酪氨酸磷酸化缺陷;(ii)抑制lps诱导的TLR4、适配蛋白TRIF和激酶TBK1之间的信号体组装;(iii) TBK1和转录因子IRF-3激活不足;(iv)负调节因子Tollip、IRAK-M、SHIP-1、SOCS-1、SARM和SIKE表达增加。我们在THP1细胞和人单核细胞中的初步数据显示,LPS诱导的c-Src和Lyn磷酸化以及Lyn- tlr4相互作用减少;抑制IRAK4和TAK-1激酶的激活;k63关联的IRAK1和TRAF-6多泛素化功能受损;抑制泛素化IRAK1与TRAF6和IKK3的相互作用;A20的表达增加,A20是一种关键的去泛素化酶。此外,我们发现蛋白酪氨酸磷酸酶的抑制或A20基因的敲低降低了LPS耐受性诱导,这表明酪氨酸磷酸化和k63连锁多泛素化的改变在耐受性中起着至关重要的作用。基于这些数据,我们假设LPS耐受性改变了TLR4、Mal和IRAK激酶的翻译后修饰,并增加了TLR信号传导的负调节因子水平,从而通过改变近端信号体组成导致TLR应答的重编程。这一假设将在以下具体目标中进行检验:鉴定参与TLR4和Mal磷酸化的激酶和磷酸酶,并确定脂多糖耐受性对其表达和活性的影响;2. 确定LPS耐受性改变信号小体组装和近端适配器激酶模块激活的机制;和3。阐明与LPS耐受相关的负调控分子干扰TLR4信号的分子基础。这些研究将确定耐受的新机制,并确定受影响的关键中间体。他们将为我们未来脓毒症动物模型的体内研究和脓毒症患者的转化研究奠定基础,以促进新的治疗策略的发展,以改善脓毒症患者的治疗。这些进展对于改善美国脓毒症患者的公共健康至关重要

项目成果

期刊论文数量(16)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Asp299Gly polymorphism alters TLR4 signaling by interfering with recruitment of MyD88 and TRIF.
IRAK4 activity controls immune responses to intracellular bacteria Listeria monocytogenes and Mycobacterium smegmatis.
  • DOI:
    10.1002/jlb.2a1117-449r
  • 发表时间:
    2018-10
  • 期刊:
  • 影响因子:
    5.5
  • 作者:
    Pattabiraman G;Murphy M;Agliano F;Karlinsey K;Medvedev AE
  • 通讯作者:
    Medvedev AE
Analysis of the functional role of Toll-like receptor-4 tyrosine phosphorylation.
Toll样受体4酪氨酸磷酸化的功能作用分析。
Endotoxin Tolerance Inhibits Lyn and c-Src Phosphorylation and Association with Toll-Like Receptor 4 but Increases Expression and Activity of Protein Phosphatases.
  • DOI:
    10.1159/000440838
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    5.3
  • 作者:
    Xiong Y;Murphy M;Manavalan TT;Pattabiraman G;Qiu F;Chang HH;Ho IC;Medvedev AE
  • 通讯作者:
    Medvedev AE
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ANDREI E MEDVEDEV其他文献

ANDREI E MEDVEDEV的其他文献

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{{ truncateString('ANDREI E MEDVEDEV', 18)}}的其他基金

Long Non-Coding RNA, TLR Tolerance and Sepsis
长非编码 RNA、TLR 耐受性和脓毒症
  • 批准号:
    9297691
  • 财政年份:
    2017
  • 资助金额:
    $ 25.88万
  • 项目类别:
Role of IRAK-4 in Rheumatoid Arthritis
IRAK-4 在类风湿关节炎中的作用
  • 批准号:
    9135224
  • 财政年份:
    2015
  • 资助金额:
    $ 25.88万
  • 项目类别:
Mechanisms of Impaired Mycobacteria Sensing by TLR2 and TLR4 Polymorphic Variants
TLR2 和 TLR4 多态性变体损害分枝杆菌感应的机制
  • 批准号:
    8882763
  • 财政年份:
    2014
  • 资助金额:
    $ 25.88万
  • 项目类别:
IRAK4 and systemic lupus erythematosus
IRAK4 与系统性红斑狼疮
  • 批准号:
    8722427
  • 财政年份:
    2013
  • 资助金额:
    $ 25.88万
  • 项目类别:
IRAK4 and systemic lupus erythematosus
IRAK4 与系统性红斑狼疮
  • 批准号:
    8509341
  • 财政年份:
    2013
  • 资助金额:
    $ 25.88万
  • 项目类别:
Effect of Bacterial Tolerance on TLR4 Signal Transduction
细菌耐受性对 TLR4 信号转导的影响
  • 批准号:
    8505354
  • 财政年份:
    2011
  • 资助金额:
    $ 25.88万
  • 项目类别:
Effect of Bacterial Tolerance on TLR4 Signal Transduction
细菌耐受性对 TLR4 信号转导的影响
  • 批准号:
    8590386
  • 财政年份:
    2011
  • 资助金额:
    $ 25.88万
  • 项目类别:
Effect of Bacterial Tolerance on TLR4 Signal Transduction
细菌耐受性对 TLR4 信号转导的影响
  • 批准号:
    8187136
  • 财政年份:
    2011
  • 资助金额:
    $ 25.88万
  • 项目类别:
Effect of Bacterial Tolerance on TLR4 Signal Transduction
细菌耐受性对 TLR4 信号转导的影响
  • 批准号:
    8320085
  • 财政年份:
    2011
  • 资助金额:
    $ 25.88万
  • 项目类别:
TLR4 Mutations: Molecular Mechanisms of Impaired LPS Sensitivity
TLR4 突变:LPS 敏感性受损的分子机制
  • 批准号:
    7870345
  • 财政年份:
    2009
  • 资助金额:
    $ 25.88万
  • 项目类别:

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