Nuclear MT1-MMP and Macrophage Immune Function

核MT1-MMP与巨噬细胞免疫功能

基本信息

批准号：
8630187
负责人：
STEPHEN J WEISS
金额：
$ 38.88万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8630187
关键词：
Affect Attention Basement membrane Behavior Cell Nucleus Cell physiology Cells Chromatin Remodeling Factor Chronic Complement Connective Tissue DNA Binding Disease Disorder by Site Elements Endothelial Cells Enzymes Epithelial Cells Event Experimental Animal Model Extracellular Matrix Family member Gene Family Gene Targeting Genes Health Host Defense Human Immune Immune Response Genes Immune response In Vitro Inflammation Inflammatory Inflammatory Response Interleukin-10 Interleukin-6 Length MMP14 gene Matrix Metalloproteinases Mediating Mediator of activation protein Membrane Metalloproteinase Gene Molecular Morbidity - disease rate Mus Myeloid Cells NURF NuRD complex Nuclear Nuclear Translocation Nucleoplasm Outcome Pathway interactions Peptide Hydrolases Play Population Process Regulation Reporting Research Design Role Series Signal Transduction System TLR4 gene TNF gene Therapeutic Intervention Tissues Trans-Activators Transactivation Transcriptional Activation chemokine cytokine immune function in vitro activity in vivo insight interstitial macrophage membrane-type matrix metalloproteinase mortality novel programs promoter response trafficking

项目摘要

DESCRIPTION (provided by applicant): During events ranging from host defense to chronic inflammatory disease states, macrophages (MOs) infiltrate affected interstitial tissues where they can participate in both the proteolytic remodeling of the extracellular matrix and local immune responses. MOs have long been assumed to mobilize proteolytic enzymes (particularly those belonging to the matrix metalloproteinase gene family) in order to remodel the extracellular matrix. However, increasing evidence suggests that MMPs can also regulate cell function independently of their matrix remodeling activities. In an attempt to characterize matrix metalloproteinase-dependent versus -independent functions in MOs, we have recently focused our attention on the membrane-anchored protease, MT1-MMP - the single MMP family member whose deletion in mice results in a profound increase in morbidity and mortality. In recently reported studies designed to compare and contrast the function of wild-type and MT1- MMP-null MOs, we discovered that MO-derived MT1-MMP acts as a previously unsuspected transactivator of the gene networks central to MO inflammatory responses. MT1-MMP exerts these effects on MO function by controlling a novel regulatory axis wherein LPS-TLR4 interactions trigger MT1-MMP expression which then acts as a required activator of PI3K¿/Akt/GSK3 signaling and the Mi-2/NuRD complex of nucleosome remodeling factors. Importantly, but unexpectedly, MT1-MMP exerts control over MO immune responses by trafficking into the nuclear compartment where it associates with the PI3K¿ promoter. While similar - if not identical - processes are operative in human cells, the mechanisms that control MT1-MMP nuclear trafficking and translocation remain undefined as do the processes that control MT1-MMP-DNA binding interactions or target gene selection. Furthermore, independent of MT1-MMP function in the nuclear compartment, the proteinase also serves as a key effector of MO-mediated turnover of the extracellular matrix, particularly those components associated with basement membranes, the specialized connective tissue barriers that underlies all epithelial and endothelial cells. As such, we propose to i) characterize the regulatory mechanisms underlying MT1-MMP nuclear trafficking and nucleoplasm translocation, ii) identify the DNA-binding partners that mediate MT1-MMP-mediated nuclear transcriptional activation iii) define the role of MT1-MMP as the dominant mediator of extracellular matrix remodeling and iv) characterize the role of MO MT1-MMP in regulating immune responses in vivo. These studies should provide novel insights into newly identified, MO- dependent nucleosomal remodeling pathways that mark chronic inflammatory events central to host defense as well as inflammatory disease states. As MT-MMPs and PI3K¿ are expressed in almost all immune cell populations, these results should serve to outline a new paradigm in inflammation and identification of control mechanisms that may prove conducive to therapeutic intervention.

描述（由申请人提供）：在从宿主防御到慢性炎症状态的各种事件中，巨噬细胞（MO）渗透受影响的间质组织，在那里它们可以参与细胞外基质的蛋白水解重塑和局部免疫反应。动员蛋白水解酶（特别是属于基质金属蛋白酶基因家族的蛋白水解酶）以重塑细胞外基质。然而，越来越多的证据表明 MMP 也可以。为了描述 MO 中基质金属蛋白酶依赖性与非依赖性功能的特征，我们最近将注意力集中在膜锚定蛋白酶 MT1-MMP（其缺失的单一 MMP 家族成员）上。在最近报道的旨在比较和对比野生型和 MT1-MMP-null MO 的功能的研究中，我们发现 MO 衍生的 MT1-MMP。 MT1-MMP 作为 MO 炎症反应核心基因网络的反式激活因子，通过控制新的调节轴对 MO 功能产生影响，因此 LPS-TLR4 相互作用触发 MT1-MMP 表达，然后充当 PI3K 所需的激活剂。 ¿ /Akt/GSK3 信号传导和核小体重塑因子的 Mi-2/NuRD 复合物重要但出人意料的是，MT1-MMP 通过转运到与 PI3K 结合的核区室来控制 MO 免疫反应。虽然类似（如果不相同）的过程在人类细胞中起作用，但控制 MT1-MMP 核运输和易位的机制仍然未定义，控制 MT1-MMP-DNA 结合相互作用或靶基因选择的过程也是如此。除了核区室中 MT1-MMP 功能的影响外，蛋白酶还充当 MO 介导的细胞外基质周转的关键效应器，特别是与基底膜相关的那些成分，基底膜是所有上皮细胞和上皮细胞的特殊结缔组织屏障。因此，我们建议 i) 表征 MT1-MMP 核运输和核质易位的调控机制，ii) 识别介导 MT1-MMP 介导的核转录激活的 DNA 结合伙伴，iii) 定义 MT1 的作用。 -MMP 作为细胞外基质重塑的主要介质，并且 iv) 描述了 MO MT1-MMP 在调节体内免疫反应中的作用。这些研究应该为新发现的 MO-提供新的见解。依赖的核小体重塑途径，标志着对宿主防御以及炎症疾病状态至关重要的慢性炎症事件。几乎在所有免疫细胞群中都有表达，这些结果应该有助于勾勒出炎症的新范式，并确定可能有助于治疗干预的控制机制。