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Endothelial‐immune crosstalk contributes to vasculopathy in nonalcoholic fatty liver disease
Author(s) -
Ng ChunYi,
Lee Khang Leng,
Muthiah Mark Dhinesh,
Wu Kan Xing,
Chioh Florence Wen Jing,
Tan Konstanze,
Soon Gwyneth Shook Ting,
Shabbir Asim,
Loo Wai Mun,
Low Zun Siong,
Chen Qingfeng,
Wahli Walter,
Tan Nguan Soon,
Ng Huck Hui,
Dan Yock Young,
Cheung Christine
Publication year - 2022
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202154271
Subject(s) - nonalcoholic fatty liver disease , immune system , chemokine , endothelial stem cell , immunology , crosstalk , cxcr4 , biology , medicine , cancer research , fatty liver , disease , biochemistry , physics , optics , in vitro
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.