MMP-dependent control of 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，单核细胞/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。当M长期以来，人们一直认为骨髓细胞动员蛋白水解酶（特别是那些属于基质金属蛋白酶基因家族的蛋白水解酶）以穿过细胞外基质屏障，越来越多的证据表明，骨髓细胞群通过依赖于细胞形状的机械变形的不依赖于蛋白酶的过程渗透组织。因此，虽然MO表达基质金属蛋白酶，但这些酶的功能仍不清楚。在试图确定替代基质金属蛋白酶依赖功能的MO，我们已经把注意力集中在膜锚定蛋白酶，MT 1-MMP。在初步研究中，旨在比较和对比野生型和MT 1-MMP-null MO的组织侵袭行为，我们发现，MO衍生的MT 1-MMP并不像预测的那样，在体外或体内调节细胞运输中发挥所需的作用。相反，MT 1-MMP+/+与MT 1-MMP-/-MO的基因表达谱表明，蛋白酶作为MO炎症反应中心基因网络的关键但未被怀疑的反式激活因子。有证据表明，MT 1-MMP可能通过控制迄今未描述的轴发挥这种作用，其中LPS-TLR 4相互作用触发MT 1-MMP表达，然后作为PI 3 K？Akt/GSK 3信号传导和核小体重塑因子的Mi-2/NuRD复合物。结合一个额外的机构的初步数据支持的可能性，MT 1-MMP交通到核隔室，我们假设MT 1-MMP作为共转录激活剂的免疫调节至关重要。因此，我们建议i）表征体外MT 1-MMP-/-巨噬细胞中LPS-TLR 4轴的功能状态，ii）定义连接PI 3 K？Akt-GSK 3信号传导至Mi-2/NuRD依赖性核小体重塑，iii）表征控制MO免疫应答的MT-MMP核运输途径。这些研究应该提供新的和新颖的见解，以配合MO依赖性细胞外基质周转与核小体重塑途径，标志着慢性炎症事件中央宿主防御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, monocytes/macrophages (MOs) infiltrate affected interstitial tissues where they can participate in both the proteolytic remodeling of the extracellular matrix and local immune responses. While M¿s have long been assumed to mobilize proteolytic enzymes (particularly those belonging to the matrix metalloproteinase gene family) in order to traffic through extracellular matrix barriers, increasing evidence suggests that myeloid cell populations infiltrate tissues via protease-independent processes relying instead on the mechanical distortion of cell shape. Hence, while MOs express matrix metalloproteinases, the function of these enzymes remain unclear. In an attempt to identify alternate matrix metalloproteinase-dependent functions in MOs, we have focused our attention on the membrane-anchored protease, MT1-MMP. In preliminary studies designed to compare and contrast the tissue-invasive behavior of wild-type and MT1-MMP-null MOs, we find that MO-derived MT1-MMP does not, as predicted, play a required role in regulating cell trafficking in vitro or in vivo. Instead, gene expression profiling of MT1-MMP+/+ versus MT1-MMP-/- MOs suggest that the protease acts as a critical but unsuspected, transactivator of the gene networks central to MO inflammatory responses. Evidence suggests that MT1-MMP may exert this effect by controlling a heretofore undescribed 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. In combination with an additional body of preliminary data supporting the possibility that MT1-MMP traffics into the nuclear compartment, we postulate that MT1-MMP serves as co-transcriptional activators critical to immune regulation. As such, we propose to i) characterize the functional status of the LPS-TLR4 axis in MT1-MMP-/- macrophages in vitro, ii) define the MT-MMP-initiated cascades that link PI3K?-Akt-GSK3 signaling to Mi-2/NuRD-dependent nucleosome remodeling, iii) characterize the MT-MMP nuclear trafficking pathway that control MO immune responses. These studies should provide new and novel insights into the orchestration of MO-dependent extracellular matrix turnover with the 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.