Differentiation/migratory fate of monocyte-derived cells

描述(由申请人提供)：一些炎症性疾病可能会成为慢性疾病，至少部分原因是正常情况下导致炎症消退的事件失败。我们和其他人发现了动脉粥样硬化以失败的解决方案为特征的证据。然而，为了充分了解炎症过程是如何在动脉粥样硬化等慢性疾病中出错的，必须了解导致急性炎症健康消退的过程。一般说来，中性粒细胞通过局部的细胞凋亡从炎症部位基本清除。单核细胞来源的细胞也可以经历局部的凋亡，但介导其清除的主要机制被认为是通过淋巴管从炎性病灶向引流淋巴结的迁移。然而，这种单核细胞来源的细胞在急性炎症期间的命运模型是基于有限的证据，主要来自一项跟踪这些吞噬细胞在急性炎症的整个过程中的研究。这项研究和其他相关研究是在腹膜腔中进行的，腹膜腔是一种特殊的解剖空间，可以允许巨噬细胞以非特异性的方式向大网膜和其他邻近组织输出。因此，在大多数其他器官中，可能对迁移出口有更严格的要求，从炎症部位移除单核细胞来源的细胞可能较少依赖于迁移到淋巴结，或者只有一小部分单核细胞来源的细胞可能具有迁移到淋巴管的能力。事实上，目前还没有关于单核细胞的两个主要亚群是否通过不同的机制从炎症部位清除的信息。根据我们过去的工作和目前的初步数据，我们假设单核细胞来源的细胞从消炎部位迁出需要发展出一种与Gr1lo单核细胞非常相似的表型，即“非经典”CCR2loCX3CR1hi单核细胞亚群。我们预测，Gr1lo单核细胞来源的细胞很容易从炎症部位清除，确实是结构性地首先通过组织，然后不断地通过淋巴，以产生不同的CD11cint淋巴结节细胞群，这可能对应于历史上被称为“淋巴面纱细胞”的树突状细胞。目前尚不清楚Gr1hi单核细胞来源的细胞在分解过程中是否通过淋巴管迁移；我们假设它们在淋巴中的迁移需要转换为Gr1lo单核细胞来源的细胞表型，这种转换可能取决于炎症部位的适当信号。在这里，我们将跟踪单核细胞亚群在容易消退的急性炎症模型(目标1)、稳态淋巴分析(目标2)和动脉粥样硬化(消退失败的模型3)中的命运。

DESCRIPTION (provided by applicant): Some inflammatory diseases may become chronic due, at least in part, to a failure of events that normally bring about resolution of inflammation. We, and others, find evidence that atherosclerosis is characterized by failed resolution programs. However, in order to fully understand how inflammatory processes go awry in chronic diseases like atherosclerosis, it is imperative to understand the processes that bring about healthy resolution of acute inflammation. In general, neutrophils are largely cleared from sites of inflammation by local apoptosis. Monocyte-derived cells can also undergo local apoptosis, but the major mechanism mediating their clearance is thought to be emigration from the inflammatory focus to the draining lymph node through lymphatic vessels. This model for the fate of monocyte-derived cells during acute inflammation is, however, based on limited evidence, mainly derived from one study that tracked these phagocytes during the full course of acute inflammation. This and other related studies were carried out in the peritoneal cavity, a specialized anatomic compartment that can allow egress of macrophages to the omentum and other adjacent tissue in a nonspecific manner. Thus, in most other organs where more stringent requirements for migratory egress likely apply, removal of monocyte-derived cells from inflammatory sites may depend less upon emigration to lymph nodes, or only a subset of monocyte-derived cells may have the capacity to emigrate into lymphatic vessels. Indeed, no information is available on whether the two major subsets of monocytes are cleared from sites of inflammation by different mechanisms. Based on our past work and current preliminary data, we hypothesize that the emigration of monocyte-derived cells from sites of resolving inflammation requires development of a phenotype closely resembling Gr1lo monocytes, the "nonclassical" CCR2loCX3CR1hi monocyte subset. We predict that Gr1lo monocyte-derived cells are readily cleared from sites of inflammation and indeed constitutively traffic first through tissue and then lymph continuously to give rise to a distinct population of CD11cint lymph node cells that may correspond to the dendritic cells historically termed "lymph veiled cells." It is less clear whether Gr1hi monocyte-derived cells emigrate through lymphatics during resolution; we hypothesize that their migration through lymph requires conversion to a Gr1lo monocyte-derived cell phenotype and this conversion may depend upon appropriate signals at the site of inflammation. Here we will track the fate of monocyte subsets in models of acute inflammation that readily resolve (aim 1), analysis in steady state lymph (aim 2), and atherosclerosis, a model of failed resolution (aim 3).