L-selectin shedding affects bacterial clearance in the lung: a new regulatory pathway for integrin outside-in signaling
L-selectin shedding affects bacterial clearance in the lung: a new regulatory pathway for integrin outside-in signaling
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DOI：
10.1182/blood.2019000685
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发表时间：
2019-10-24
期刊：
影响因子：
20.3
通讯作者：
Zarbock, Alexander
中科院分区：
文献类型：
--
作者：
Cappenberg, Anika;Margraf, Andreas;Zarbock, Alexander
革兰阴性菌肺炎是一种常见病、多发病、病死率高的严重疾病。细菌病原体的消除依赖于中性粒细胞的募集和功能。粘附分子L-选择素最近被认为参与了中性粒细胞中的整合素激活（由内而外的信号传导）。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，L-选择素缺陷型小鼠与野生型对照组相比更容易发生肺部感染。从机制上讲，由整合素接合触发的L-选择素从中性粒细胞表面裂解涉及中性粒细胞募集到肺中和细菌清除。在整合素连接的下游，金属蛋白酶A解整合素和金属蛋白酶17（ADAM 17）以IRhom 2依赖性方式从嗜中性粒细胞表面脱落L-选择素。L-选择素裂解增强整合素介导的由外向内信号传导，导致中性粒细胞效应子功能增加。因此，我们确定了一种新的调节机制，在中性粒细胞所需的充分的免疫反应所引发的整合素参与肺炎克雷伯菌诱导的肺部炎症。
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.