Regulation of inflammation: sheddases and CD62L

炎症是消除病原体的基本过程，但它也在导致 疾病(例如，炎症和心血管疾病之间的关系得到很好的确立，通过这种关系 炎症既是其原因，也是其结果)。中性粒细胞是最突出的白细胞。 早期炎症反应的组成部分及其从血液中的募集被放大和延长 由白细胞黏附蛋白L-选择素(CD62L)表达。适当地，L-选择素受到高度调控，这 涉及其非常迅速的胞外区域从白细胞表面分裂(脱落)。高水平的可溶性L- 正常人血清中的选择素证明这是一个生理过程。当白细胞被激活时， ADAM17是L-选择素和其他调节白细胞因子的主要脱氧酶 炎症(如肿瘤坏死因子、肿瘤坏死因子受体和肿瘤坏死因子受体II)。目前，我们在认识上存在重大差距 这一蛋白降解过程是如何调节的以及ADAM17的S在中性粒细胞分泌L-选择素中的作用 细胞外渗和细胞凋亡。因此，我们的目标是确定L背后的监管机制-- 选择素脱落。我们的总体假设是L-选择素的脱落受多种分子的调控 以及细胞活动。反过来，这些事件似乎以不同的方式控制白细胞的募集，例如 L-选择素对中性粒细胞与血管壁黏附的影响及维持 血清中可溶性L-选择素作为黏附缓冲液。这项研究的目标是确定 ADAM17是L-选择素脱落所必需的，它定义了调控L-选择素的机制 通过直接检查ADAM17以及确定其在表面的空间分布来确定其脱落 中性粒细胞的黏附(目的2)，并阐明ADAM17在诱导L- 选择素脱落，如中性粒细胞凋亡(目标3)。我们的战略将涉及创新概念和 方法，包括使用和操纵人中性粒细胞和成熟白细胞缺乏 功能ADAM17.这项研究将有助于回答白细胞细胞生物学中的基本问题 并将为炎症调控的关键方面提供新的见解。这一知识将是 在开发针对炎症过程量身定做的更具体的治疗方法方面非常有用 豁免权。

Inflammation is an essential process to eliminate pathogens, but it also has a fundamental role in causing disease (e.g. a relationship between inflammation and cardiovascular disease is well established, by which inflammation both contributes to its cause and results from it). Neutrophils are the most prominent leukocyte component of early inflammatory responses and their recruitment from the blood is amplified and prolonged by the leukocyte adhesion protein L-selectin (CD62L). Appropriately, L-selectin is highly regulated, which involves its very rapid ectodomain cleavage from the leukocyte surface (shedding). High levels of soluble L- selectin in normal serum of humans demonstrate this is a physiological process. Upon leukocyte activation, ADAM17 is the primary sheddase of L-selectin as well as of other leukocyte factors that modulate inflammation (e.g. TNF, TNFRI, and TNFRII). Currently, there are significant gaps in our understanding of how this proteolyitic process is regulated and of ADAM17's role in L-selectin shedding during neutrophil extravasation and apoptosis. Therefore, our goal is to determine the underlying regulatory mechanisms of L- selectin shedding. Our overall hypothesis is that L-selectin shedding is modulated by a variety of molecular and cellular events. In turn, these events appear to control leukocyte recruitment in different ways, such as by influencing L-selectin adhesiveness upon neutrophil attachment to the vascular wall and by maintaining soluble L-selectin in the serum as an adhesion buffer. The goals of this study are to determine the regions of ADAM17 that are essential for L-selectin shedding (Aim 1), define the mechanisms that modulate L-selectin shedding by examining ADAM17 directly as well as determining their spatial distribution on the surface of neutrophils undergoing adhesion (Aim 2), and elucidate the role of ADAM17 in other means of inducing L- selectin shedding, such as neutrophil apoptosis (Aim 3). Our strategy will involve innovative concepts and approaches, including the use and manipulation of human neutrophils and mature leukocytes deficient in functional ADAM17. This research will help to answer fundamental questions in the cell biology of leukocyte adhesion and will provide new insights in to key aspects of inflammation regulation. This knowledge will be highly useful in the development of more specific therapies tailored to inflammatory processes and immunity.