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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

批准号：
9884735
负责人：
Ann Marshak-Rothstein
金额：
$ 20.94万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-05 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9884735
关键词：
Address Animal Model Apoptosis Autoantibodies Autoimmune Diseases Autoimmunity Automobile Driving B-Lymphocytes Basement membrane Binding Biopsy CASP8 gene CCL8 gene Cell Death Cells Cessation of life Chimeric Proteins Clinical Cutaneous Data Dendritic Cells Deposition Dermal Dermatitis Development Disease Exhibits Flare Functional disorder Gene Expression Gene Targeting Generations Goals Hematopoietic Histologic Immunosuppressive Agents In Vitro Inflammation Inflammatory Interferon Type II Interleukin-17 Langerhans cell Ligands Lupus MHC Class II Genes Membrane Modeling Molecular Chaperones Mus Mutation Myeloid Cells Pathogenesis Pathway interactions Patients Process Production Psoriasis Radiation Chimera Recurrence Regulation Reproducibility Role Signal Pathway Signal Transduction Site Skin Structure of germinal center of lymph node System T-Lymphocyte TLR7 gene Th1 Cells Tissues Treatment Efficacy UV Radiation Exposure Up-Regulation Work chemokine cytokine draining lymph node effector T cell human disease in vivo insight keratinocyte lupus cutaneous lupus-like mouse model novel patient population prevent protein expression radioresistant response side effect skin lesion skin organogenesis small molecule inhibitor therapeutic target trafficking

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