Effect of Neutrophil Priming on Chemotaxis and Signaling

外周血中性粒细胞向感染部位的迁移包括整合素在 ？2个家庭。中性粒细胞使用这些整合素黏附在感染附近的内皮细胞上，并 随后转至细胞外基质，以引导其向病原体导航。2整合素 CR3(CD11b/CD18)是一种独特的受体，因为它有两个不同的配体结合部位，I-结构域 识别细胞黏附分子、补体成分和细胞外基质；以及凝集素结构域 它结合碳水化合物，如葡聚糖和那些在糖基磷脂酰肌醇锚定的碳水化合物 感受器。β-葡聚糖是(1，3)(1，6)-β-D-键中葡萄糖部分的聚合物，通常被发现为 真菌细胞壁的结构成分，是CR3凝集素位点的功能激动剂。在当前的 资助期我们发现，许多依赖CR3的中性粒细胞功能在 对连接I-结构域、凝集素位点或两者的反应。在此提出了实验方案 继续确定机制/S解释单个受体如何转导如此不同的 当连接在不同的结合部位时，细胞会产生影响。 这项建议的具体目标是：(一)确定城市轨道交通的动态调控和空间定位 CR3在I结构域和凝集素位点的差异激活；(Ii)确定信号转导 人中性粒细胞活化后由随机迁移向定向迁移的途径 确定CR3凝集素位点的激活在体内对宿主防御的作用。 鉴于CR3在白细胞功能的各个方面的重要性，更好地理解这种复合体 控制其功能的调节机制可能会导致更好地治疗 这是由于它的失调造成的。多动可导致自身免疫性疾病、多发性 硬化症、炎症性肠病、牛皮癣和关节炎。功能不足可导致复发 感染和伤口愈合不好。靶向CR3的疗法可能被开发成安全有效 增强手术前或癌症患者或创伤、脓毒症、创伤后患者的白细胞功能 衰老或免疫抑制。这项提议的基本前提是更好地理解 白细胞整合素的调节可能揭示整合素是安全有效的治疗靶点 调节先天免疫系统。

The emigration of peripheral blood neutrophils to a site of infection includes a central role of integrins within the ¿2 family. Neutrophils use these integrins to adhere to endothelial cells located in the vicinity of infection and subsequently to extracellular matrix in order to guide their navigation towards the pathogen. The ¿2 integrin CR3 (CD11b/CD18) is a unique receptor in that it has two distinct ligand binding sites, the I-domain which recognizes cell adhesion molecules, complement components and extracellular matrix; and the lectin domain which binds carbohydrate such as ¿-glucan and those expressed on glycosylphosphatidyl inositol-anchored receptors. Beta-glucan is a polymer of glucose moieties in (1,3)(1,6)-beta-D-linkages found normally as a structural component of the fungal cell wall and is a functional agonist of the CR3 lectin site. During the current funding period we found than a number of CR3-dependent neutrophil functions are regulated differently in response to ligation of the I-domain, the lectin site, or both together. Experiments are proposed in this continuation to determine the mechanism/s that explain how a single receptor can transduce such different cellular affects when ligated at its distinct binding sites. The specific aims of this proposal are: (I) to determine the dynamic regulation and spatial localization of CR3 upon differential activation of the I-domain and the lectin site; (II) to determine the signal transduction pathways that mediate the conversion of random to directed migration of human neutrophils upon activation of the CR3 lectin site; (III) to determine the role of CR3 lectin site activation on host defense in vivo. Given the importance of CR3 in every aspect of leukocyte function, a better understanding of the complex regulatory mechanisms that control its function may lead to better treatment of the pathological conditions that result from its dysregulation. Hyperactivity can lead to pathologies such as autoimmune diseases, multiple sclerosis, inflammatory bowel disease, psoriasis, and arthritis. Insufficient function can result in recurrent infection and failure to heal wounds. Therapies that target CR3 may be developed to safely and effectively enhance leukocyte function in presurgical or cancer patients or those following trauma, sepsis, wounding, aging or immunosuppression. The underlying premise of this proposal is that a better understanding of leukocyte integrin regulation may reveal that integrins represent therapeutic targets for safe and effective regulation of the innate immune system.