Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Muenster, Germany.
Department of Biology, Texas A&M University, College Station, TX.
Blood. 2019 Oct 24;134(17):1445-1457. doi: 10.1182/blood.2019000685.
Pneumonia induced by Gram-negative bacteria is a common and serious disease associated with high morbidity and mortality. Elimination of bacterial pathogens relies on the recruitment and functions of neutrophils. The adhesion molecule L-selectin has recently been implicated in integrin activation in neutrophils (inside-out signaling). However, the molecular mechanism by which L-selectin participates in host defense against Klebsiella pneumoniae-induced pulmonary inflammation is unknown. We demonstrate that L-selectin-deficient mice are prone to pulmonary infection compared with wild-type controls. Mechanistically, L-selectin cleavage from the neutrophil surface triggered by integrin engagement is involved in neutrophil recruitment into the lung and bacterial clearance. Downstream of integrin ligation, the metalloproteinase A disintegrin and metalloproteinase 17 (ADAM17) sheds L-selectin from the neutrophil surface in an IRhom2-dependent manner. L-selectin cleavage enhances integrin-mediated outside-in signaling, resulting in increased neutrophil effector functions. Thus, we identify a novel regulatory mechanism in neutrophils required for an adequate immune response triggered by integrin engagement during K pneumoniae-induced pulmonary inflammation.
由革兰氏阴性细菌引起的肺炎是一种常见且严重的疾病，与高发病率和死亡率相关。消除细菌病原体依赖于中性粒细胞的募集和功能。粘附分子 L-选择素最近被牵连到中性粒细胞整合素激活（内-外信号转导）中。然而，L-选择素参与宿主防御肺炎克雷伯菌诱导的肺部炎症的分子机制尚不清楚。我们证明，与野生型对照相比，L-选择素缺陷小鼠更容易发生肺部感染。从机制上讲，整合素结合触发的中性粒细胞表面 L-选择素的切割参与了中性粒细胞向肺部的募集和细菌清除。整合素连接的下游，金属蛋白酶 ADAM17（金属蛋白酶 A 去整合素和金属蛋白酶 17）以 IRhom2 依赖的方式从中性粒细胞表面脱落 L-选择素。L-选择素的切割增强了整合素介导的外-内信号转导，导致中性粒细胞效应功能增加。因此，我们确定了一种新型的中性粒细胞调节机制，该机制在肺炎克雷伯菌诱导的肺部炎症中整合素结合触发的适当免疫反应中是必需的。
