Nuclear MT1-MMP and Macrophage Immune Function

描述（由申请方提供）：在从宿主防御到慢性炎症性疾病状态的事件期间，巨噬细胞（MO）浸润受影响的间质组织，它们可以参与细胞外基质的蛋白水解重塑和局部免疫应答。长期以来，MO被认为是动员蛋白水解酶（特别是那些属于基质金属蛋白酶基因家族），以重塑细胞外基质。然而，越来越多的证据表明，MMPs也可以独立于其基质重塑活动调节细胞功能。在试图表征基质金属蛋白酶依赖与非依赖功能的MO，我们最近把我们的注意力集中在膜锚定蛋白酶，MT 1-MMP -单一的MMP家族成员，其在小鼠中的删除导致发病率和死亡率的大幅增加。在最近报道的旨在比较和对比野生型和MT 1-MMP-null MO的功能的研究中，我们发现MO衍生的MT 1-MMP作为先前未被怀疑的MO炎症反应中心基因网络的反式激活因子。MT 1-MMP通过控制新的调节轴对MO功能发挥这些作用，其中LPS-TLR 4相互作用触发MT 1-MMP表达，其然后充当PI 3 K κ/Akt/GSK 3信号传导和核小体重塑因子的Mi-2/NuRD复合物的所需激活剂。重要的是，但出乎意料的是，MT 1-MMP通过运输到与PI 3 K启动子相关的核区室来控制MO免疫应答。虽然类似的-如果不是相同的-过程在人类细胞中起作用，控制MT 1-MMP核运输和易位的机制仍然不确定，控制MT 1-MMP-DNA结合相互作用或靶基因选择的过程也是如此。此外，不依赖于MT 1-MMP在核区室中的功能，蛋白酶也作为MO介导的细胞外基质周转的关键效应物，特别是与基底膜相关的那些组分，基底膜是所有上皮细胞和内皮细胞下面的特化结缔组织屏障。因此，我们建议i）表征MT 1-MMP核运输和核质易位的调控机制，ii）鉴定介导MT 1-MMP介导的核转录激活的DNA结合配偶体，iii）定义MT 1-MMP作为细胞外基质重塑的主要介质的作用，iv）表征MO MT 1-MMP在体内调节免疫应答中的作用。这些研究应该为新鉴定的MO依赖性核小体重塑途径提供新的见解，这些途径标志着对宿主防御至关重要的慢性炎症事件以及炎症性疾病状态。作为MT-MMPs和PI 3 K在几乎所有的免疫细胞群体中表达，这些结果应该有助于概述炎症和识别控制机制的新范例，这些机制可能被证明有利于治疗干预。

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.