Chronic pulmonary colonization with bacterial pathogens, particularly Pseudomonas aeruginosa, is the primary cause of morbidity and mortality in patients with cystic fibrosis (CF). We observed that β1-integrins accumulate on the luminal membrane of upper-airway epithelial cells from mice and humans with CF. β1-integrin accumulation is due to increased ceramide and the formation of ceramide platforms that trap β1-integrins on the luminal pole of bronchial epithelial cells. β1-integrins downregulate acid ceramidase expression, resulting in further accumulation of ceramide and consequent reduction of surface sphingosine, a lipid that kills bacteria. Interrupting this vicious cycle by triggering surface β1-integrin internalization via anti-β1-integrin antibodies or the RGD peptide ligand—or by genetic or pharmacological correction of ceramide levels—normalizes β1-integrin distribution and sphingosine levels in CF epithelial cells and prevents P. aeruginosa infection in CF mice. These findings suggest a therapeutic avenue to ameliorate CF-associated bacterial infections.

细菌病原体的慢性肺部定植，特别是铜绿假单胞菌，是囊性纤维化 (CF) 患者发病和死亡的主要原因。我们观察到 β1-整合素积聚在患有 CF 的小鼠和人类的上气道上皮细胞的腔膜上。β1-整合素的积累是由于增加的神经酰胺和神经酰胺平台的形成，这些平台将β1-整合素捕获在支气管上皮细胞的腔极上。β1-整合素下调酸性神经酰胺酶的表达，导致神经酰胺的进一步积累和表面鞘氨醇的减少，这是一种杀死细菌的脂质。通过抗β1-整合素抗体或RGD肽配体触发表面β1-整合素内化，或通过神经酰胺水平的遗传或药理学校正来中断这种恶性循环，使CF上皮细胞中的β1-整合素分布和鞘氨醇水平正常化，并防止CF 小鼠中的铜绿假单胞菌感染。这些发现表明了一种改善 CF 相关细菌感染的治疗途径。