Macrophage-derived exosomal aminopeptidase N aggravates sepsis-induced acute lung injury by regulating necroptosis of lung epithelial cell.
Macrophage-derived exosomal aminopeptidase N aggravates sepsis-induced acute lung injury by regulating necroptosis of lung epithelial cell.
复制标题
巨噬细胞源性外泌体氨基肽酶N通过调节肺上皮细胞坏死凋亡加重脓毒症诱导的急性肺损伤。
DOI：
10.1038/s42003-022-03481-y
复制
发表时间：
2022-06-06
影响因子：
5.9
通讯作者：
中科院分区：
文献类型：
--
作者：
脓毒症引起的急性肺损伤（acute lung injury，ALI）是脓毒症的一种严重并发症，是脓毒症的主要致死原因。循环血浆外泌体可能在调节免疫细胞和结构细胞之间的细胞间通讯以及促成脓毒症相关器官损伤中发挥关键作用。然而，外泌体介导的细胞间信号转导加重脓毒性感染中ALI的分子机制仍不明确。因此，我们研究了巨噬细胞来源的外泌体APN/CD 13对诱导上皮细胞坏死的影响。发现脓毒症小鼠和脓毒症ALI患者血浆中的外泌体APN/CD 13水平较高。此外，血浆外泌体APN/CD 13水平升高与脓毒症患者ALI的严重程度和死亡率相关。我们发现APN/CD 13在LPS刺激的巨噬细胞分泌的外泌体中显著高表达。此外，c-Myc直接诱导APN/CD 13表达并包装到exosomes中。最后，巨噬细胞外泌体APN/CD 13通过与细胞表面受体TLR 4结合，诱导ROS产生、线粒体功能障碍和NF-κB活化，调节肺上皮细胞的坏死性凋亡。这些结果表明，巨噬细胞分泌的外泌体APN/CD 13可以以APN/CD 13依赖的方式触发上皮细胞坏死性凋亡，这为脓毒症诱导的ALI中上皮细胞功能紊乱的机制提供了见解。脓毒症诱导的急性肺损伤患者和小鼠循环血浆外泌体中氨肽酶N水平调节肺上皮细胞的坏死
Sepsis-induced acute lung injury (ALI) is a serious sepsis complication and the prevailing cause of death. Circulating plasma exosomes might exert a key role in regulating intercellular communication between immunological and structural cells, as well as contributing to sepsis-related organ damage. However, the molecular mechanisms by which exosome-mediated intercellular signaling exacerbate ALI in septic infection remains undefined. Therefore, we investigated the effect of macrophage-derived exosomal APN/CD13 on the induction of epithelial cell necrosis. Exosomal APN/CD13 levels in the plasma of septic mice and patients with septic ALI were found to be higher. Furthermore, increased plasma exosomal APN/CD13 levels were associated with the severity of ALI and fatality in sepsis patients. We found remarkably high expression of APN/CD13 in exosomes secreted by LPS-stimulated macrophages. Moreover, c-Myc directly induced APN/CD13 expression and was packed into exosomes. Finally, exosomal APN/CD13 from macrophages regulated necroptosis of lung epithelial cells by binding to the cell surface receptor TLR4 to induce ROS generation, mitochondrial dysfunction and NF-κB activation. These results demonstrate that macrophage-secreted exosomal APN/CD13 can trigger epithelial cell necroptosis in an APN/CD13-dependent manner, which provides insight into the mechanism of epithelial cell functional disorder in sepsis-induced ALI. Necroptosis of lung epithelial cells is regulated by aminopeptidase N levels in circulating plasma exosomes in patients and mice with sepsis-induced acute lung injury.
登录
查看更多内容
DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
DOI：
10.4049/jimmunol.1403133
发表时间：
2015-05-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ghosh M;Subramani J;Rahman MM;Shapiro LH
通讯作者：
Shapiro LH
影响因子：
24.1
作者：
Bertheloot D;Latz E;Franklin BS
通讯作者：
Franklin BS
DOI：
10.1042/cs20200573
发表时间：
2021-01-29
期刊：
Clinical science (London, England : 1979)
影响因子：
--
作者：
Gao M;Yu T;Liu D;Shi Y;Yang P;Zhang J;Wang J;Liu Y;Zhang X
通讯作者：
Zhang X
肺上皮细胞来源的 IL-25 负向调节 LPS 诱导的巨噬细胞外泌体释放
影响因子：
21.1
作者：
Li ZG;Scott MJ;Brzóska T;Sundd P;Li YH;Billiar TR;Wilson MA;Wang P;Fan J
通讯作者：
Fan J