Abstract
Reactive oxygen species (ROS) contribute to the development of non-alcoholic fatty liver disease. ROS generation by infiltrating macrophages involves multiple mechanisms, including Toll-like receptor 4 (TLR4)-mediated NADPH oxidase (NOX) activation. Here, we show that palmitate-stimulated CD11b+F4/80low hepatic infiltrating macrophages, but not CD11b+F4/80high Kupffer cells, generate ROS via dynamin-mediated endocytosis of TLR4 and NOX2, independently from MyD88 and TRIF. We demonstrate that differently from LPS-mediated dimerization of the TLR4–MD2 complex, palmitate binds a monomeric TLR4–MD2 complex that triggers endocytosis, ROS generation and increases pro-interleukin-1β expression in macrophages. Palmitate-induced ROS generation in human CD68lowCD14high macrophages is strongly suppressed by inhibition of dynamin. Furthermore, Nox2-deficient mice are protected against high-fat diet-induced hepatic steatosis and insulin resistance. Therefore, endocytosis of TLR4 and NOX2 into macrophages might be a novel therapeutic target for non-alcoholic fatty liver disease.
Highlights
Reactive oxygen species (ROS) contribute to the development of non-alcoholic fatty liver disease
We have demonstrated that palmitate binds a monomeric Toll-like receptor 4 (TLR4)–MD2 complex in CD11b+F4/80high and CD68lowCD14high macrophages of mice and humans, respectively, which leads to NOX2-mediated ROS generation by dynamin-mediated endocytosis of the TLR4–MD2 complex
Another striking finding was that the high-fat diet (HFD) or palmitateinduced ROS generation and pro-inflammatory changes selectively appeared in transmigrating liver macrophages and not in resident Kupffer cells
Summary
Reactive oxygen species (ROS) contribute to the development of non-alcoholic fatty liver disease. Diet-induced obesity is commonly associated with nonalcoholic fatty liver disease (NAFLD) and insulin resistance, in which recruited immune cells such as macrophages, neutrophils, lymphocytes, mast cells and eosinophils contribute to a pro-inflammatory environment[1, 2] Of these cells, recruited macrophages and resident Kupffer cells secrete diverse cytokines including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β, which contribute to insulin resistance in hepatocytes by upregulating the activation of inhibitor of κB kinase-β/nuclear factor-κB (NF-κB) and c-Jun Nterminal kinase (JNK)/activator protein-12–4. We report that in CD11b+F4/80low hepatic macrophages, palmitate triggers the endocytosis of a monomeric TLR4–MD2 complex, leading to NOX2 activation and ROS generation, which play an obligatory role in diet-induced hepatic steatosis and insulin resistance These findings provide novel pathophysiological insights and therapeutic targets for NAFLD
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
