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

Abstract

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.

Angiopoietin-like 4 shapes the intrahepatic T-cell landscape via eIF2α signaling during steatohepatitis in diet-induced NAFLD

“…These abnormal immune responses are predominantly orchestrated by CD4 + helper T cells, which are highly activated throughout the early and advanced NASH stages in the LIDPAD model. This corroborates findings that T-lymphocytes are heavily involved in NAFLD deterioration( 38–40 ). A recent study also identified an integral role of activated CD4 + T cells at fibrotic sites in NASH-driven hepatic inflammation and fibrosis( 41 ).…”

“…This model supports a liver-pancreas axis that promotes compensatory pancreatic islet cell hyperplasia, a phenomenon similarly observed in animal models of insulin resistance( 35 ) and in humans, where there is a clear correlation between BMI and β-cell mass( 36 ) and thereafter fatty liver and the development of type-2 diabetes( 37 ). Furthermore, LIDPAD mice also displayed NAFLD-associated vasculopathy, with heightened endothelial expression of CXCL12 in the aortas and the liver vasculature( 38 ). These various metabolic dysfunctions and extrahepatic comorbidities are collectively absent in current NAFLD models.…”

Decoding the role of immune T cells: A new territory for improvement of metabolic‐associated fatty liver disease

“…However, it is worth noting that Treg disorder is attributed to the development of MAFLD‐associated HCC (MAFLD‐HCC) from MAFLD. The clinical data showed that patients with moderate MAFLD‐HCC had a higher level of Treg cells to suppress host antitumor immunity and dramatically facilitate the initiation and progression of cancer [ 98 ]. Butyrate, a metabolite of gut microbiota from MAFLD‐HCC patients, led to Treg cells amplification meanwhile reduced CD8 + T cells and B cells quantity via enhancing Foxp3 expression and restraining proinflammatory cytokines to reinforce immunosuppressive response of peripheral blood mononuclear cells (PBMC) from non‐MAFLD individuals [ 98 ].…”

Elucidating the genetic architecture of DNA methylation to identify promising molecular mechanisms of disease

“…Nonetheless, we demonstrated that mQTLs identified in other studies 16,17 , including those identified in a cross-ancestry analysis 17 , were well replicated in our database. We captured whole blood-based DNA methylation profiles, which can serve as candidate biomarkers for diseases; however, they may not reflect tissue-specific 35 . MR analysis was used to showcase the potential application of our mQTL database; however, MR analysis is based on assumptions that may not be testable 36 .…”