The role of TLRs, Type II IFN and Type III IFN in a Murine Model of Autoinflammation

TLR、II 型 IFN 和 III 型 IFN 在小鼠自身炎症模型中的作用

基本信息

项目摘要

ABSTRACT Common pathophysiological mechanisms are thought to promote the cutaneous and systemic manifestations of lupus. Thus a better understanding of the factors that promote CLE are likely to provide important insights as far as the pathogenesis of SLE. Nevertheless, it is also likely that tissue specific effector mechanisms account for the diverse clinical presentations exhibited by SLE patient populations. Since 75% of SLE patients exhibit skin lesions of some sort, and UV exposure of the skin is often associated with lupus flares, it is surprising that there have been relatively few mechanistic studies that address initiation, progression and recurrence of CLE. One reason for this gap is that murine models available for the study of CLE have been limited – despite the numerous murine models of SLE, models that accurately reflect the central features of CLE are much more limited. We have now develop an inducible model of lupus like skin inflammation (LLSI), initiated by T cell transfer, that recapitulates many of the features of CLE. These include a prominent role for skin-infiltrating IFNγ-producing Th1 cells, excessive keratinocyte death, autoantibody deposition at the dermal/epidermal border, increased expression of CxCL9, CxCL10, CxCL11, CCL8, and accumulation of pDCs in the skin. There are also mechanistic similarities between our LLSI model and other inducible as well as genetically programmed murine models of SLE; they all depend on the expression of TLR7 and are exacerbated by the absence of TLR9. Therefore our LLSI mice provide a novel, rapid and reproducible system for exploring the effector mechanisms responsible for the induction and regulation of cutaneous lupus. This application will focus on TLR9 and FasL. As mentioned, TLR9 negatively regulates the development of both cutaneous and systemic lupus, but whether TLR9 works passively by simply competing with TLR7 for access to the endosomal trafficking chaperone Unc93B1, or actively by inducing molecules dependent on a TLR9 signaling cascade that limit inflammation, has not been addressed. We have also recently shown that the development of skin lesions is completely dependent T cell FasL expression, but whether FasL promotes disease indirectly by inducing cell death and creating cell debris and/or directly by inducing the production of pro-inflammatory cytokines is unresolved. Interplay between TLR9 and FasL may be an important amplification loop in LLSI - TLR ligands induce upregulation of Fas and FasL generates cell debris that can activate endosomal TLRs. We propose to address the questions by using gene-targeted mice with discriminating mutations for both in vitro and in vivo (LLSI) studies. In Aim 1, we will use mice that express normal levels of a form of TLR9 that cannot engage MyD88, and in Aim 2, we will use mice that express a Caspase 8 mutation which removes the Caspase 8 autocleavage site and thereby prevents FasL-induced apoptosis but not chemokine production. Together, these studies should help identify the most effective therapeutic strategies for targeting TLR9 and FasL pathways to prevent or ameliorate the development of cutaneous lupus.
摘要

项目成果

期刊论文数量(0)
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Ann Marshak-Rothstein其他文献

Ann Marshak-Rothstein的其他文献

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{{ truncateString('Ann Marshak-Rothstein', 18)}}的其他基金

The role of TLRs, Type II IFN and Type III IFN in a Murine Model of Autoinflammation
TLR、II 型 IFN 和 III 型 IFN 在小鼠自身炎症模型中的作用
  • 批准号:
    10375346
  • 财政年份:
    2021
  • 资助金额:
    $ 49.49万
  • 项目类别:
Mechanisms by which TLR9-deficiency and FasL Promote Cutaneous Lupus
TLR9 缺陷和 FasL 促进皮肤狼疮的机制
  • 批准号:
    9884735
  • 财政年份:
    2019
  • 资助金额:
    $ 49.49万
  • 项目类别:
Mechanisms by which TLR9-deficiency and FasL Promote Cutaneous Lupus
TLR9 缺陷和 FasL 促进皮肤狼疮的机制
  • 批准号:
    9752064
  • 财政年份:
    2019
  • 资助金额:
    $ 49.49万
  • 项目类别:
Distinct Functional Outcomes of BCR/TLR7 and BCR/TLR9 Co-engagement
BCR/TLR7 和 BCR/TLR9 共同参与的不同功能结果
  • 批准号:
    9228925
  • 财政年份:
    2015
  • 资助金额:
    $ 49.49万
  • 项目类别:
Distinct Functional Outcomes of BCR/TLR7 and BCR/TLR9 Co-engagement
BCR/TLR7 和 BCR/TLR9 共同参与的不同功能结果
  • 批准号:
    9033830
  • 财政年份:
    2015
  • 资助金额:
    $ 49.49万
  • 项目类别:
Activation of B Cells by Host Toll-Like Receptor Ligands
宿主 Toll 样受体配体激活 B 细胞
  • 批准号:
    8504902
  • 财政年份:
    2013
  • 资助金额:
    $ 49.49万
  • 项目类别:
CO-FUNDING-NIAID
联合资助-NIAID
  • 批准号:
    8504901
  • 财政年份:
    2013
  • 资助金额:
    $ 49.49万
  • 项目类别:
Activation of B Cells by Host Toll-Like Receptor Ligands
宿主 Toll 样受体配体激活 B 细胞
  • 批准号:
    8378438
  • 财政年份:
    2012
  • 资助金额:
    $ 49.49万
  • 项目类别:
CO-FUNDING-NIAID
联合资助-NIAID
  • 批准号:
    8378436
  • 财政年份:
    2012
  • 资助金额:
    $ 49.49万
  • 项目类别:
Activation of B Cells by Host Toll-Like Receptor Ligands
宿主 Toll 样受体配体激活 B 细胞
  • 批准号:
    8290052
  • 财政年份:
    2011
  • 资助金额:
    $ 49.49万
  • 项目类别:

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用于癌症免疫治疗的三信号人工抗原呈递细胞
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    2022
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