Endothelial‐immune crosstalk contributes to vasculopathy in nonalcoholic fatty liver disease

• Published in: EMBO reports Vol. 23; no. 6; pp. e54271 - n/a
• Main Authors: Ng, Chun‐Yi, 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.06.2022; Springer Nature B.V; John Wiley and Sons Inc
• Subjects: Animal models; Animals; Antibodies; Antigens; Blood vessels; CD8 antigen; Cell Movement; chemokine ligand‐receptor interaction; Chemokines; Chemotaxis; circulating endothelial cells; Crosstalk; CXCL12 protein; CXCR4 protein; Damage detection; Diet; Effector cells; EMBO19; EMBO24; EMBO46; Endothelial cells; Endothelial Cells - metabolism; endothelial dysfunction; Fatty liver; Humans; Immune system; immunoprofiling; Leukocyte migration; Leukocytes; Liver; Liver - metabolism; Liver diseases; Lymphocytes; Lymphocytes - metabolism; Lymphocytes T; Mice; Non-alcoholic Fatty Liver Disease - metabolism; Patients; Signal Transduction; transcriptomics; Vascular diseases; chemokine ligand‐receptor interaction; transcriptomics; endothelial dysfunction; circulating endothelial cells; immunoprofiling; chemokine ligand-receptor interaction
• ISSN: 1469-221X; 1469-3178; 1469-3178
• DOI: 10.15252/embr.202154271

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. Synopsis Endothelial chemokine activation is evident in non‐alcoholic fatty liver disease patients and mouse diet‐induced disease models. The CXCL12‐CXCR4 axis mediates the interaction of patient endothelial cells with effector immune cells, potentially leading to vascular injury. NAFLD patient‐derived endothelial cells exhibit increased chemokine hallmarks and human leukocyte antigens. Aortas and liver vasculatures of diet‐induced NAFLD mice show increased endothelial CXCL12 and leukocyte infiltration. Inhibition of the CXCL12‐CXCR4 axis diminishes chemotaxis of CD8 + T cells and endothelial barrier impairment. NAFLD patients manifest elevated levels of circulating damaged endothelial cells. Graphical Abstract Endothelial chemokine activation is evident in non‐alcoholic fatty liver disease patients and mouse diet‐induced disease models. The CXCL12‐CXCR4 axis mediates the interaction of patient endothelial cells with effector immune cells, potentially leading to vascular injury.