Myeloid-derived suppressor cells (MDSCs

Nonalcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA), endoplasmic reticulum (ER) stress, and hepatocyte lipoapoptosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 5 (DR5) is significantly elevated in patients with nonalcoholic steatohepatitis, and steatotic hepatocytes demonstrate increased sensitivity to TRAIL-mediated cell death. Nonetheless, a role for TRAIL and/or DR5 in mediating lipoapoptotic pathways is unexplored. Here, we examined the contribution of DR5 death signaling to lipoapoptosis by free fatty acids. The toxic saturated free fatty acid palmitate induces an increase in DR5 mRNA and protein expression in Huh-7 human hepatoma cells leading to DR5 localization into lipid rafts, cell surface receptor clustering with subsequent recruitment of the initiator caspase-8, and ultimately cellular demise. Obesity and insulin resistance, cardinal features of the metabolic syndrome, are associated with enhanced lipolysis in adipose tissue (1, 2). This excessive lipolysis results in increased serum concentrations of free fatty acids (FFA), 2 augmenting their delivery to non-adipose tissues such as liver, heart, and pancreatic ␤-cells (2). Inundation of these tissues with FFA overwhelms fatty acid oxidative pathways with toxic cellular consequences. An advanced response to toxic FFA is cellular demise by apoptosis, termed lipoapoptosis (3). Hepatocyte lipotoxicity is particularly germane to injury in the liver, where it contributes to the syndrome of nonalcoholic fatty liver disease (NAFLD) (4). For example, the magnitude of hepatocyte lipoapoptosis correlates with hepatic disease severity (4). Thus, the mechanisms initiating lipoapoptosis are of biomedical interest and human health relevance. Lipotoxicity is likely multifactorial. Sustained endoplasmic reticulum (ER) stress (5-7), c-Jun N-terminal kinase (JNK) activation (8, 9), and oxidative stress (10) have all been implicated in lipotoxicity. Despite the fact that death receptors are potent mediators of cytotoxicity (11), especially in hepatic diseases, their contribution to lipotoxicity is incompletely defined. Fas, the prototype death receptor, has been implicated in adipocyte toxicity and inflammation (12), and its hepatic expression is increased in NAFLD (4). Tumor necrosis factor-␣ (TNF-␣) and TNF receptor-1 (TNFR-1) have also been implicated in hepatic steatosis (13)(14)(15). In contrast, the role of TNF-related apoptosis-inducing ligand (TRAIL) and its cognate death receptors (DR)-4 and -5 in lipotoxicity is understudied. Yet, increasing data implicate a critical role for DR5 in lipotoxicity. For example, DR5 expression is increased in steatotic hepatocytes and sensitizes hepatocytes to exogenous TRAIL cytotoxicity (16). Thus, the role of DR5 in lipoapoptosis merits further investigation.In this study, we explored the potential contribution of DR5 death signaling during lipoapoptosis by saturated FFA. The results implicate TRAIL death signaling by DR...

Preclinical data support the potential of the death-signaling receptors for TRAIL as targets for cancer therapy. However, it is unclear whether these death-signaling receptors suppress the emergence and growth of malignant tumors in vivo. Herein we show that TNF-related apoptosis-inducing ligand receptor (TRAIL-R), the only proapoptotic death-signaling receptor for TRAIL in the mouse, suppresses inflammation and tumorigenesis. Loss of a single TRAIL-R allele on the lymphoma-prone Eμ-myc genetic background significantly reduced median lymphoma-free survival. TRAIL-R-deficient lymphomas developed with equal frequency irrespective of mono-or biallelic loss of TRAIL-R, had increased metastatic potential, and showed apoptotic defects relative to WT littermates. In addition, TRAIL-R -/-mice showed decreased long-term survival following a sublethal dose of ionizing radiation. Histological evaluation of moribund irradiated TRAIL-R -/-animals showed hallmarks of bronchopneumonia as well as tumor formation with increased NF-κB p65 expression. TRAIL-R also suppressed diethylnitrosamine-induced (DEN-induced) hepatocarcinogenesis, as an increased number of large tumors with apoptotic defects developed in the livers of DEN-treated TRAIL-R -/-mice. Thus TRAIL-R may function as an inflammation and tumor suppressor in multiple tissues in vivo.

DR5 (also called TRAIL receptor 2 and KILLER) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (also called TRAIL and Apo2 ligand). DR5 is a transcriptional target of p53, and its overexpression induces cell death in vitro. However, the in vivo biology of DR5 has remained largely unexplored. To better understand the role of DR5 in development and in adult tissues, we have created a knockout mouse lacking DR5. This mouse is viable and develops normally with the exception of having an enlarged thymus. We show that DR5 is not expressed in developing embryos but is present in the decidua and chorion early in development. DR5-null mouse embryo fibroblasts expressing E1A are resistant to treatment with TRAIL, suggesting that DR5 may be the primary proapoptotic receptor for TRAIL in the mouse. When exposed to ionizing radiation, DR5-null tissues exhibit reduced amounts of apoptosis compared to wild-type thymus, spleen, Peyer's patches, and the white matter of the brain. In the ileum, colon, and stomach, DR5 deficiency was associated with a subtle phenotype of radiation-induced cell death. These results indicate that DR5 has a limited role during embryogenesis and early stages of development but plays an organ-specific role in the response to DNA-damaging stimuli.

Background & Aims Low-grade chronic inflammation is a cardinal feature of the metabolic syndrome, yet its pathogenesis is not well defined. The purpose of this study was to examine the role of TRAIL receptor (TR) signaling in the pathogenesis of obesity-associated inflammation utilizing mice with the genetic deletion of TR. Methods TR knockout (TR−/−) mice and their littermate wild-type (WT) mice were fed a diet high in saturated fat, cholesterol and fructose (FFC) or chow. Metabolic phenotyping, liver injury, and liver and adipose tissue inflammation were assessed. Chemotaxis and activation of mouse bone marrow-derived macrophages (BMDMϕ) was measured. Results Genetic deletion of TR completely repressed weight gain, adiposity and insulin resistance in FFC-fed mice. Moreover, TR−/− mice suppressed steatohepatitis, with essentially normal serum ALT, hepatocyte apoptosis and liver triglyceride accumulation. Gene array data implicated inhibition of macrophage-associated hepatic inflammation in the absence of the TR. In keeping with this, there was diminished accumulation and activation of inflammatory macrophages in liver and adipose tissue. TR−/− BMDMϕ manifest reduced chemotaxis and diminished activation of nuclear factor-κ B signaling upon activation by palmitate and lipopolysaccharide. Conclusions These data advance the concept that macrophage-associated hepatic and adipose tissue inflammation of nutrient excess requires TR signaling.