期刊
EMBO REPORTS
卷 23, 期 6, 页码 -出版社
WILEY
DOI: 10.15252/embr.202154271
关键词
chemokine ligand-receptor interaction; circulating endothelial cells; endothelial dysfunction; immunoprofiling; transcriptomics
资金
- EMULSION consortium
- IAF-PP grant from the Agency for Science, Technology and Research (Singapore) [H18/01/a0/017]
- Nanyang Technological University Singapore [RGY0069/2019]
The top cause of mortality in patients with nonalcoholic fatty liver disease (NAFLD) is cardiovascular complications. The study reveals that blood outgrowth endothelial cells (BOECs) from NAFLD subjects exhibit global transcriptional upregulation of chemokines and human leukocyte antigens. T cell intensification is observed in NAFLD patients. CXCL12-neutralizing antibody treatment helps to moderate the enhanced chemotactic effect of NAFLD BOECs in recruiting CD8(+) T lymphocytes.
The top cause of mortality in patients with nonalcoholic fatty liver disease (NAFLD) is cardiovascular complications. However, mechanisms of NAFLD-associated vasculopathy remain understudied. Here, we show that blood outgrowth endothelial cells (BOECs) from NAFLD subjects exhibit global transcriptional upregulation of chemokines and human leukocyte antigens. In mouse models of diet-induced NAFLD, we confirm heightened endothelial expressions of CXCL12 in the aortas and the liver vasculatures, and increased retention of infiltrated leukocytes within the vessel walls. To elucidate endothelial-immune crosstalk, we performed immunoprofiling by single-cell analysis, uncovering T cell intensification in NAFLD patients. Functionally, treatment with a CXCL12-neutralizing antibody is effective at moderating the enhanced chemotactic effect of NAFLD BOECs in recruiting CD8(+) T lymphocytes. Interference with the CXCL12-CXCR4 axis using a CXCR4 antagonist also averts the impact of immune cell transendothelial migration and restores endothelial barrier integrity. Clinically, we detect threefold more circulating damaged endothelial cells in NAFLD patients than in healthy controls. Our work provides insight into the modulation of interactions with effector immune cells to mitigate endothelial injury in NAFLD.
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