Mechanisms by which TLR9-deficiency and FasL Promote Cutaneous Lupus

TLR9 缺陷和 FasL 促进皮肤狼疮的机制

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.
抽象的 常见的病理生理机制被认为促进皮肤和全身表现 狼疮。因此,更好地了解促进 CLE 的因素可能会提供重要的见解: 就SLE的发病机制而言。然而,组织特异性效应机制也可能解释了这一点。 针对 SLE 患者群体表现出的不同临床表现。由于 75% 的 SLE 患者表现出 某种类型的皮肤损伤,并且皮肤的紫外线暴露通常与狼疮发作有关,令人惊讶的是 针对 CLE 的发生、进展和复发的机制研究相对较少。 造成这一差距的原因之一是可用于 CLE 研究的小鼠模型有限——尽管 SLE 小鼠模型众多,准确反映 CLE 核心特征的模型还有更多 有限的。我们现在开发了一种由 T 细胞引发的狼疮样皮肤炎症 (LLSI) 的诱导模型 转移,概括了 CLE 的许多功能。其中包括皮肤渗透的重要作用 产生 IFNγ 的 Th1 细胞、角质形成细胞过度死亡、自身抗体沉积在真皮/表皮 边界,CxCL9、CxCL10、CxCL11、CCL8 表达增加以及皮肤中 pDC 的积累。那里 我们的 LLSI 模型与其他诱导模型和遗传模型之间也存在机械相似性 SLE 的编程小鼠模型;它们都依赖于 TLR7 的表达,并因 TLR7 的表达而加剧 TLR9 缺失。因此,我们的 LLSI 小鼠提供了一种新颖、快速且可重复的系统来探索 负责诱导和调节皮肤狼疮的效应机制。该应用程序将 重点关注 TLR9 和 FasL。如前所述,TLR9 负向调节皮肤和皮肤的发育。 系统性狼疮,但 TLR9 是否只是通过简单地与 TLR7 竞争访问 内体运输伴侣 Unc93B1,或通过依赖 TLR9 信号传导的分子主动诱导 限制炎症的级联反应尚未得到解决。我们最近还表明,发展 皮肤病变的发生完全依赖于T细胞FasL表达,但FasL是否间接促进病变 通过诱导细胞死亡和产生细胞碎片和/或直接通过诱导促炎物质的产生 细胞因子尚未解决。 TLR9 和 FasL 之间的相互作用可能是 LLSI 中重要的放大环路 - TLR 配体诱导 Fas 上调,FasL 产生可激活内体 TLR 的细胞碎片。我们 建议通过使用具有区分性突变的基因靶向小鼠来解决这些问题 和体内(LLSI)研究。在目标 1 中,我们将使用表达正常水平 TLR9 形式的小鼠,而这种 TLR9 形式不能表达正常水平。 参与 MyD88,在目标 2 中,我们将使用表达 Caspase 8 突变的小鼠,该突变消除了 Caspase 8 自动切割位点,从而阻止 FasL 诱导的细胞凋亡,但不能阻止趋化因子的产生。 总之,这些研究应有助于确定针对 TLR9 和 TLR9 的最有效的治疗策略。 FasL 途径可预防或改善皮肤狼疮的发展。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Ann Marshak-Rothstein其他文献

Ann Marshak-Rothstein的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:
    10576930
  • 财政年份:
    2021
  • 资助金额:
    $ 20.94万
  • 项目类别:
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:
    $ 20.94万
  • 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:
    $ 20.94万
  • 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:
    $ 20.94万
  • 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:
    $ 20.94万
  • 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:
    $ 20.94万
  • 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:
    $ 20.94万
  • 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:
    $ 20.94万
  • 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:
    $ 20.94万
  • 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:
    $ 20.94万
  • 项目类别:

相似海外基金

Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
  • 批准号:
    495434
  • 财政年份:
    2023
  • 资助金额:
    $ 20.94万
  • 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
  • 批准号:
    10586596
  • 财政年份:
    2023
  • 资助金额:
    $ 20.94万
  • 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
  • 批准号:
    10590479
  • 财政年份:
    2023
  • 资助金额:
    $ 20.94万
  • 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
  • 批准号:
    10642519
  • 财政年份:
    2023
  • 资助金额:
    $ 20.94万
  • 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
  • 批准号:
    23K06011
  • 财政年份:
    2023
  • 资助金额:
    $ 20.94万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
  • 批准号:
    10682117
  • 财政年份:
    2023
  • 资助金额:
    $ 20.94万
  • 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
  • 批准号:
    10708517
  • 财政年份:
    2023
  • 资助金额:
    $ 20.94万
  • 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
  • 批准号:
    10575566
  • 财政年份:
    2023
  • 资助金额:
    $ 20.94万
  • 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
  • 批准号:
    23K15696
  • 财政年份:
    2023
  • 资助金额:
    $ 20.94万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
  • 批准号:
    23K15867
  • 财政年份:
    2023
  • 资助金额:
    $ 20.94万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了