Anti-inflammatory role of MUC1 mucin

描述（由申请方提供）：铜绿假单胞菌（PA）是一种机会性细菌病原体，可引起许多临床上重要的肺部疾病，包括肺炎和囊性纤维化（CF）。 在CF的情况下，患病患者中发病率和死亡率的主要原因是由于存在被PA严重感染的粘稠且坚韧的粘液而导致的气道阻塞。 由于PA暴露发生在正常和CF个体的呼吸系统中，CF患者中该病原体的“选择性”感染表明存在非CF气道中不存在的致病机制。 许多不同的理论已被提出来解释CF的病因。 本实验室观察到气道上皮细胞表面的MUC 1粘蛋白是PA通过鞭毛蛋白介导的特异性结合位点。MUC 1糖蛋白的结构表明，它作为一种受体，在与鞭毛蛋白相互作用后在细胞内传递信号。 使用基因修饰的小鼠阻断MUC 1表达（MUC 1基因敲除小鼠），我们的初步研究表明，与野生型小鼠相比，Muc 1基因敲除小鼠表现出增加的PA从肺部的清除率和更大的气道白细胞的招募和更高水平的促炎细胞因子在支气管肺泡灌洗液PA鞭毛刺激。 有趣的是，TLR 5是另一种细胞表面受体，在与鞭毛蛋白结合后产生细胞内信号传导途径。 基于这种相似性，我们进行了额外的实验来研究MUC 1和TLR 5之间的功能关系。 我们观察到MUC 1的表达抑制正常肺细胞中的鞭毛蛋白-TLR 5信号通路，但不抑制CF气道上皮细胞。 基于这些结果，我们形成了MUC 1是抗炎细胞表面受体的假设，其至少部分地通过拮抗鞭毛蛋白-TLR 5信号传导起作用。 在这个提议中，我们将通过确定MUC 1减弱TLR 5信号转导的机制来测试我们的理论。 该项目的成功完成将为MUC 1在炎症，先天免疫和CF中PA感染的早期阶段中的作用提供重要的见解。

DESCRIPTION (provided by applicant): Pseudomonas aeruginosa (PA) is an opportunistic bacterial pathogen responsible for a number of clinically important lung diseases including pneumonia and cystic fibrosis (CF). In the case of CF, the major cause of morbidity and mortality among afflicted patients is airway obstruction due to the presence of thick and tenacious mucus that becomes heavily infected with PA. Because PA exposure occurs in the respiratory system of both normal and CF individuals, "selective"' infection by this pathogen among CF patients suggests the presence of a disease-causing mechanism that is not present in non-CF airways. A number of different theories have been proposed to account for the etiology of CF. Our laboratory made the interesting observation that MUC1 mucin on the surface of airway epithelial cells is a specific binding site for PA mediated through bacterial flagellin. The structure of the MUC1 glycoprotein suggests that it acts as a receptor to transmit signals intracellularly following interaction with flagellin. Using mice genetically modified to block MUC1 expression (MUC1 knockout mice), our preliminary studies showed that, compared with wild type mice, Muc1 knockout animals exhibited increased PA clearance from the lungs and greater recruitment of airway leukocytes and higher levels of the proinflammatory cytokines in bronchoalveolar lavage fluid following PA flagellin stimulation. Interestingly, TLR5 is another cell surface receptor that generates an intracellular signaling pathway following binding to flagellin. Based on this similarity, we conducted additional experiments to investigate the functional relationship between MUC1 and TLR5. We observed that expression of MUC1 inhibited the flagellin-TLR5 signaling pathway in normal lung cells but not CF airway epithelial cells. Based on these results, we formed the hypothesis that MUC1 is an anti-inflammatory cell surface receptor that acts, at least in part, through antagonism of flagellin-TLR5 signaling. In this proposal, we will test our theory by determining the mechanisms by which MUC1 attenuates TLR5 signal transduction. Successful completion of this project will provide important insights for the role of MUC1 in inflammation, innate immunity, and the early stages of PA infection in CF.