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，至少部分原因是通常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的特征是解决方案失败的证据。然而，为了充分了解炎症过程如何在动脉粥样硬化等慢性疾病中出错，必须了解导致急性炎症健康解决的过程。一般来说，中性粒细胞主要通过局部凋亡从炎症部位清除。单核细胞衍生的细胞也可以经历局部细胞凋亡，但介导其清除的主要机制被认为是通过淋巴管从炎症病灶迁移到引流淋巴结。然而，这种急性炎症期间单核细胞衍生细胞命运的模型基于有限的证据，主要来自一项在急性炎症的整个过程中追踪这些吞噬细胞的研究。这项研究和其他相关研究是在腹膜腔中进行的，腹膜腔是一种专门的解剖隔室，可以允许巨噬细胞以非特异性方式进入网膜和其他邻近组织。因此，在大多数其他器官中，对迁移出口可能有更严格的要求，从炎症部位清除单核细胞来源的细胞可能不太依赖于迁移到淋巴结，或者只有一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，没有关于单核细胞的两个主要亚群是否通过不同机制从炎症部位清除的信息。基于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解决炎症的网站移民需要开发一个表型非常相似的Gr 1 lo单核细胞，“非经典”CCR 2loCX 3CR 1hi单核细胞亚群。我们预测，Gr 1 lo单核细胞来源的细胞很容易从炎症部位清除，并且确实组成性地首先通过组织，然后连续地通过淋巴，产生不同的CD 11 cint淋巴结细胞群体，其可能对应于历史上称为“淋巴面纱细胞”的树突状细胞。目前尚不清楚Gr 1hi单核细胞衍生的细胞是否在消退过程中通过淋巴细胞迁移;我们假设它们通过淋巴的迁移需要转化为Gr 1 lo单核细胞衍生的细胞表型，这种转化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急性炎症模型中的命运，这些模型很容易解决（目标1），在稳态淋巴液中的分析（目标2），以及动脉粥样硬化，一个失败的解决模型（目标3）。

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).