Endothelial Cell‐Derived Extracellular Vesicles Promote Aberrant Neutrophil Trafficking and Subsequent Remote Lung Injury

• Published in: Advanced science 2024-10, Vol.11 (38), p.e2400647-n/a
• Main Authors: Zi, Shuang‐Feng, Wu, Xiao‐Jing, Tang, Ying, Liang, Yun‐Peng, Liu, Xu, Wang, Lu, Li, Song‐Li, Wu, Chang‐De, Xu, Jing‐Yuan, Liu, Tao, Huang, Wei, Xie, Jian‐Feng, Liu, Ling, Chao, Jie, Qiu, Hai‐Bo
• Format: Article
• Language: English
• Subjects: ALI/ARDS; Blood vessels; endothelial cells; Extracellular vesicles; Genotype & phenotype; Inflammation; Lungs; Mortality; Multiple organ dysfunction syndrome; Neutrophils; Sepsis; Signal transduction
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202400647

The development of acute respiratory distress syndrome (ARDS) in sepsis is associated with substantial morbidity and mortality. However, the molecular pathogenesis underlying sepsis‐induced ARDS remains elusive. Neutrophil heterogeneity and dysfunction contribute to uncontrolled inflammation in patients with ARDS. A specific subset of neutrophils undergoing reverse transendothelial migration (rTEM), which is characterized by an activated phenotype, is implicated in the systemic dissemination of inflammation. Using single‐cell RNA sequencing (scRNA‐seq), it identified functionally activated neutrophils exhibiting the rTEM phenotype in the lung of a sepsis mouse model using cecal ligation and puncture. The prevalence of neutrophils with the rTEM phenotype is elevated in the blood of patients with sepsis‐associated ARDS and is positively correlated with disease severity. Mechanically, scRNA‐seq and proteomic analys revealed that inflamed endothelial cell (EC) released extracellular vesicles (EVs) enriched in karyopherin subunit beta‐1 (KPNB1), promoting abluminal‐to‐luminal neutrophil rTEM. Additionally, EC‐derived EVs are elevated and positively correlated with the proportion of rTEM neutrophils in clinical sepsis. Collectively, EC‐derived EV is identified as a critical regulator of neutrophil rTEM, providing insights into the contribution of rTEM neutrophils to sepsis‐associated lung injury. It is shown that endothelial cell (EC)‐derived extracellular vesicles (EVs) promote the reverse transendothelial migration (rTEM) of PMNs with a highly activated phenotype, contributing to distant lung injury during sepsis. Mechanistically, this aberrant response is caused by degradation of junctional adhesion molecule‐C (JAM‐C) at EC junctions by neutrophil elastase (NE), partially mediated by KPNB1 contained in inflamed EC‐derived EVs.