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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

批准号：
10576930
负责人：
Ann Marshak-Rothstein
金额：
$ 49.49万
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：
2021
资助国家：
美国
起止时间：
2021-03-19 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576930
关键词：
Address Antigen-Presenting Cells Attention Autoantibodies Autoimmune Diseases B-Lymphocytes Brain CASP8 gene CCL8 gene Categories Cell Death Cell Death Induction Cell Lineage Cells Central Nervous System Diseases Cessation of life Chronic Clinical Cutaneous DNA Data Defect Deoxyribonucleases Dependence Deposition Dermal Development Disease Endosomes Environment Epithelial Cells Exhibits Extramedullary Hematopoiesis Fibrosis Flare Flow Cytometry Future Gene Targeting Goals Hepatocyte Heterogeneity Immune In Vitro Induction of Apoptosis Infant Infiltration Inflammation Inflammatory Interferon Type II Interferons Knock-out Knockout Mice Ligands Liver Fibrosis Lupus Macrophage Memory Mendelian disorder Mitochondrial RNA Modeling Molecular Chaperones Mus Mutation Myelogenous Myeloid Cell Activation Myocarditis Nucleic Acids Organ Pathogenesis Pathogenicity Pathway interactions Patients Pattern recognition receptor Phenotype Play Production Proteins Pulmonary Fibrosis Recurrence Regulation Reproducibility Ribosomal RNA Role Serum Signal Transduction Site Skin Sorting System Systemic Lupus Erythematosus T-Cell Activation T-Lymphocyte TLR7 gene Testing Th1 Cells Therapeutic Tissues UV Radiation Exposure Up-Regulation Work autoinflammation autoinflammatory autoinflammatory diseases cytokine ds-DNA exhaustion gain of function mutation human disease in vivo insight keratinocyte loss of function lupus cutaneous lupus-like mouse model neutrophil novel nuclease patient population prevent pseudotoxoplasmosis syndrome receptor sensor skin lesion skin organogenesis targeted treatment therapeutic target therapeutically effective trafficking transcriptome sequencing type I interferon receptor

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