1] University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2].
1] University of North Carolina-Chapel Hill, 7011 Thurston-Bowles Building, Chapel Hill, North Carolina 27599, USA [2].
Nature. 2014 Jan 16;505(7483):412-6. doi: 10.1038/nature12807. Epub 2013 Dec 8.
Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b(-/-) mice. By contrast, in mice that transgenically overexpress Muc5b, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.
呼吸道表面每天都会接触到数十亿的颗粒物和病原体。一层保护性黏液屏障通过黏液纤毛清除（MCC）来捕获并清除它们。然而，过多的黏液会导致短暂的呼吸道感染，并引发许多呼吸道疾病。MUC5AC 和 MUC5B 是进化上保守的基因，它们编码结构相关的黏蛋白糖蛋白，是气道黏液中的主要大分子。遗传变异与多种肺部疾病有关，但 MUC5AC 和 MUC5B 在 MCC 中的具体作用以及它们抑制的持久影响尚不清楚。在这里，我们发现，Muc5b（而非 Muc5ac）对于 MCC、控制气道和中耳感染以及维持小鼠肺部免疫稳态是必需的，而 Muc5ac 则是可有可无的。Muc5b 缺乏会导致上、下呼吸道物质的积累。这种缺陷导致多种细菌（包括金黄色葡萄球菌）的慢性感染，并导致炎症无法正常消退。凋亡的巨噬细胞积累，吞噬作用受损，白细胞介素-23（IL-23）的产生减少，这些都在 Muc5b(-/-) 小鼠中发生。相比之下，在过表达 Muc5b 的转基因小鼠中，巨噬细胞功能得到改善。现有的观念将哮喘和慢性阻塞性肺疾病（COPD）中的黏液表型定义为 MUC5AC 增加所致，而气道表面的 MUC5B 水平要么不受影响，要么增加。然而，在许多患者中，气道表面的 MUC5B 产生减少了多达 90%。通过区分 Muc5b 在 MCC 中的特定作用，并确定其对小鼠细菌感染和炎症的影响，我们的研究结果为设计靶向治疗以控制黏蛋白分泌和恢复 MCC 提供了一个更精细的框架。
