Immunometabolic roles of macrophages in hepatic steatosis and insulin resistance
Reactive oxygen species (ROS) contribute to the development of non-alcoholic fatty liver disease including hepatic steatosis. Interestingly, palmitate-stimulated hepatic macrophages generate ROS via dynamin-mediated endocytosis of Toll-like receptor 4 (TLR4) and NADPH oxidase 2 (NOX2). This is independent from the myeloid differentiation primary response 88 (MyD88) and TIR-domain-containing adaptor-inducing interferon-β (TRIF). Surprisingly, differently from LPS-mediated dimerization of the TLR4-MD2 complex, palmitate directly binds a monomeric TLR4-MD2 complex that triggers endocytosis, ROS generation and increases pro-interleukin-1β expression in macrophages. Indeed, NOX2-deficient mice are protected against a high-fat diet-induced hepatic steatosis and insulin resistance. Therefore, endocytosis of TLR4 and NOX2 into macrophages might signify a novel therapeutic target for non-alcoholic fatty liver disease.
Diet-induced obesity is commonly associated with non-alcoholic fatty liver disease (NAFLD) and insulin resistance, in which recruited immune cells contribute to a pro-inflammatory environment. 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. This is achieved by upregulating the activation of inhibitor of κB kinase-β/nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK)/activator protein-1. In this process, increased plasma levels of saturated free fatty acids (FFAs), such as palmitic acids, trigger proinflammatory signals through Toll-like receptor 2 (TLR2) and TLR4 in macrophages.
Reactive oxygen species (ROS) are one of the major causes in steatohepatitis, and insulin resistance. Infiltrated macrophages generate ROS by multiple mechanisms including mitochondria damage, endoplasmic reticulum stress, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs). In liver resident Kupffer cells and infiltrating macrophages, NOX2-derived ROS stimulates them to produce pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β, in response to various factors including oxidized low-density lipoprotein (LDL) and lipopolysaccharide (LPS). Until now, the exact roles of NOX2 in inducing steatosis and insulin resistance in hepatic macrophages have not been clearly understood.
TLR4 plays a key role for innate immune responses and its signaling is triggered by the transfer of its ligand LPS to a TLR4-MD2 complex, which then undergoes homodimerization. This homodimer then can activate MyD88-dependent or MyD88-independent pathways. In addition to LPS, TLR4 can bind a wide range of ligands including FFAs. The mechanisms underlying TLR4 binding to diverse agonist are not clear. While the obesity-related increase in circulating FFA promotes the development of hepatic steatosis and insulin resistance, the precise molecular mechanisms involved in the interplay among FFA, TLR4 and NOX2 have not been fully elucidated.
The role of NOX2 on innate immune responses has been well described in mice and humans, yet the mechanism of palmitate-mediated ROS generation via NOX2 is not well understood, especially in regard to transmigrating macrophages in the steatotic and insulin resistant liver. In the present study, we have demonstrated that palmitate binds a monomeric 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 HFD or palmitate-induced ROS generation and proinflammatory changes selectively appeared in transmigrating liver macrophages and not in resident Kupffer cells. This finding, in turn, is responsible for the obesity-related steatohepatitis and insulin resistance (Figure).
For more information, please refer to the original article:
Kim SY, Jeong WI et al., “Pro-inflammatory hepatic macrophages generate ROS through NADPH oxidase 2 via endocytosis of monomeric TLR4-MD2 complex”. Nature Communications. 2017 Dec 21;8(1):2247.
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