Endothelial-immune crosstalk contributes to vasculopathy in nonalcoholic fatty liver disease
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 transcriptio...
| Main Authors: | , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2022
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| Online Access: | https://hdl.handle.net/10356/161599 |
| _version_ | 1826126361853427712 |
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| author | 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 Tan, Nguan Soon Ng, Huck-Hui Dan, Yock Young Cheung, Christine |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences 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 Tan, Nguan Soon Ng, Huck-Hui Dan, Yock Young Cheung, Christine |
| author_sort | Ng, Chun Yi |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T06:51:25Z |
| format | Journal Article |
| id | ntu-10356/161599 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:51:25Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1615992023-02-28T17:12:38Z Endothelial-immune crosstalk contributes to vasculopathy in nonalcoholic fatty liver disease 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 Tan, Nguan Soon Ng, Huck-Hui Dan, Yock Young Cheung, Christine School of Biological Sciences Lee Kong Chian School of Medicine (LKCMedicine) National University of Singapore Institute of Molecular and Cell Biology, A*STAR Science::Biological sciences Chemokine Ligand-Receptor Interaction Circulating Endothelial Cells 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. Agency for Science, Technology and Research (A*STAR) Nanyang Technological University Published version This work is funded by an IAF-PP grant (H18/01/a0/017) from the Agency for Science, Technology and Research (Singapore) on Ensemble of Multi-disciplinary Systems and Integrated Omics for NAFLD (EMULSION) diagnostic and therapeutic discovery. The team from Nanyang Technological University Singapore was also funded by the Nanyang Assistant Professorship and Human Frontier Science Program (RGY0069/2019). 2022-09-09T06:35:57Z 2022-09-09T06:35:57Z 2022 Journal Article Ng, C. Y., Lee, K. L., Muthiah, M. D., Wu, K. X., Chioh, F. W. J., Tan, K., Soon, G. S. T., Shabbir, A., Loo, W. M., Low, Z. S., Chen, Q., Tan, N. S., Ng, H., Dan, Y. Y. & Cheung, C. (2022). Endothelial-immune crosstalk contributes to vasculopathy in nonalcoholic fatty liver disease. EMBO Reports, 23(6), e54271-. https://dx.doi.org/10.15252/embr.202154271 1469-221X https://hdl.handle.net/10356/161599 10.15252/embr.202154271 35403791 2-s2.0-85127937589 6 23 e54271 en H18/01/a0/017 RGY0069/2019 EMBO Reports © 2022 The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits useand distribution in any medium, provided the originalwork is properly cited, the use is non-commercial andno modifications or adaptations are made. application/pdf |
| spellingShingle | Science::Biological sciences Chemokine Ligand-Receptor Interaction Circulating Endothelial Cells 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 Tan, Nguan Soon Ng, Huck-Hui Dan, Yock Young Cheung, Christine Endothelial-immune crosstalk contributes to vasculopathy in nonalcoholic fatty liver disease |
| title | Endothelial-immune crosstalk contributes to vasculopathy in nonalcoholic fatty liver disease |
| title_full | Endothelial-immune crosstalk contributes to vasculopathy in nonalcoholic fatty liver disease |
| title_fullStr | Endothelial-immune crosstalk contributes to vasculopathy in nonalcoholic fatty liver disease |
| title_full_unstemmed | Endothelial-immune crosstalk contributes to vasculopathy in nonalcoholic fatty liver disease |
| title_short | Endothelial-immune crosstalk contributes to vasculopathy in nonalcoholic fatty liver disease |
| title_sort | endothelial immune crosstalk contributes to vasculopathy in nonalcoholic fatty liver disease |
| topic | Science::Biological sciences Chemokine Ligand-Receptor Interaction Circulating Endothelial Cells |
| url | https://hdl.handle.net/10356/161599 |
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