Adipose tissue macrophage dysfunction is associated with a breach of vascular integrity in NASH

作者：Markus Boesch, Andreas Lindhorst, Rita Feio‐Azevedo, Paola Brescia, Alessandra Silvestri, Matthias Lannoo, Ellen Deleus, Joris Jaekers, Halit Topal, Baki Topal, Tessa Ostyn, Marie Wallays, Lena Smets, Lukas Van Melkebeke, Anetta Härtlová, Tania Roskams, Pierre Bédossa, Jef Verbeek, Olivier Govaere, Sven Francque, Alejandro Sifrim, Thierry Voet, María Rescigno, Martin T. Gericke, Hannelie Korf, Van der Merwe · 发表于：Journal of Hepatology · 年份：2023 · DOI：10.1016/j.jhep.2023.10.039 · 被引用次数：48 · 研究领域：Liver Disease Diagnosis and Treatment、Cardiovascular Disease and Adiposity、Adipokines, Inflammation, and Metabolic Diseases

BACKGROUND & AIMS: In non-alcoholic fatty liver disease (NAFLD), monocytes infiltrate visceral adipose tissue promoting local and hepatic inflammation. However, it remains unclear what drives inflammation and how the immune landscape in adipose tissue differs across the NAFLD severity spectrum. We aimed to assess adipose tissue macrophage (ATM) heterogeneity in a NAFLD cohort. METHODS: Visceral adipose tissue macrophages from lean and obese patients, stratified by NAFLD phenotypes, underwent single-cell RNA sequencing. Adipose tissue vascular integrity and breaching was assessed on a protein level via immunohistochemistry and immunofluorescence to determine targets of interest. RESULTS: We discovered multiple ATM populations, including resident vasculature-associated macrophages (ResVAMs) and distinct metabolically active macrophages (MMacs). Using trajectory analysis, we show that ResVAMs and MMacs are replenished by a common transitional macrophage (TransMac) subtype and that, during NASH, MMacs are not effectively replenished by TransMac precursors. We postulate an accessory role for MMacs and ResVAMs in protecting the adipose tissue vascular barrier, since they both interact with endothelial cells and localize around the vasculature. However, across the NAFLD severity spectrum, alterations occur in these subsets that parallel an adipose tissue vasculature breach characterized by albumin extravasation into the perivascular tissue. CONCLUSIONS: NAFLD-related macrophage dysf...