ADAM17 protects against elastase-induced emphysema by suppressing CD62L+ leukocyte infiltration in mice
ADAM17 protects against elastase-induced emphysema by suppressing CD62L+ leukocyte infiltration in mice
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DOI：
10.1152/ajplung.00214.2019
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发表时间：
2020-06-01
影响因子：
4.9
通讯作者：
Betsuyaku, Tomoko
中科院分区：
文献类型：
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作者：
Suzuki, Shoji;Ishii, Makoto;Betsuyaku, Tomoko
肺气肿是慢性阻塞性肺病的主要表现，与吸烟引起的慢性肺部炎症有关，免疫细胞如中性粒细胞、巨噬细胞和淋巴细胞起作用。虽然基质金属蛋白酶是众所周知的，有助于肺气肿的进展。去整合素和金属蛋白酶（ADAM）家族蛋白质、其它主要金属蛋白酶在疾病发病机制中的作用在很大程度上是未知的。ADAM 17是一种主要的脱落酶，它切割各种细胞表面蛋白，包括CD 62 L，这是一种粘附分子，在促进免疫细胞迁移到炎症部位方面起着关键作用。在本研究中。我们的目的是研究ADAM 17和CD 62 L的潜在作用。弹性蛋白酶诱发的肺气肿将对照和Adam 17（flox/flox）/Mx 1-Cre（Adam 17（Delta Mx 1））小鼠（8-10周龄）用5单位的猪胰腺弹性蛋白酶进行气管内注射，并在注射后监测35天。通过分析肺组织标本的平均线性截距和组织病理学检查来评价肺泡破坏。平均线性截距数据表明，弹性蛋白酶诱导的肺气肿程度在Adam 17（Delta Mx 1）小鼠中显著更严重。此外。流式细胞术显示，Adam 17（Delta Mx 1）小鼠的CD 62 L（+）中性粒细胞、CD 62 L（+）巨噬细胞和CD 62 L（+）B淋巴细胞数量显著增加。此外，用CD 62 L中和抗体对CD 62 L（+）细胞进行药理学耗竭可改善Adam 17（Delta Mx 1）小鼠的肺气肿程度。总的来说，这些结果表明，ADAM 17可能通过蛋白水解处理免疫细胞中的CD 62 L来抑制肺气肿的进展，并且ADAM 17和CD 62 L可能是治疗肺气肿的新的治疗靶点。
Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease and is associated with chronic pulmonary inflammation caused by cigarette smoking, with contributions from immune cells such as neutrophils, macrophages, and lymphocytes. Although matrix metalloproteinases are well known to contribute to emphysema progression. the role of a disintegrin and metalloproteinase (ADAM) family proteins, other major metalloproteinases, in disease pathogenesis is largely unknown. ADAM17 is a major sheddase that cleaves various cell surface proteins, including CD62L, an adhesion molecule that plays a critical role in promoting the migration of immune cells to the site of inflammation. In the present study. we aimed to investigate the potential role of ADAM17 and CD62L. in the development of elastase-induced emphysema. Control and Adam17(flox/flox)/Mx1-Cre (Adam17(Delta Mx1)) mice (8-10 wk old) were intratracheally injected with 5 units of porcine pancreas elastase and monitored for 35 days after injection. Lung alveolar destruction was evaluated by analyzing the mean linear intercepts of lung tissue specimens and by histopathological examination. Mean linear intercepts data indicated that the degree of elastase-induced emphysema was significantly more severe in Adam17(Delta Mx1) mice. Furthermore. flow cytometry showed that CD62L(+) neutrophil, CD62L(+) macrophage, and CD62L(+) B lymphocyte numbers were significantly increased in Adam17(Delta Mx1) mice. Moreover, the pharmacological depletion of CD62L(+) cells with a CD62L-neutralizing antibody ameliorated the extent of emphysema in Adam17(Delta Mx1) mice. Collectively, these results suggest that ADAM17 possibly suppresses the progression of emphysema by proteolytically processing CD62L in immune cells and that ADAM17 and CD62L could be novel therapeutic targets for treating pulmonary emphysema.