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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
TRAIL receptor deletion in mice suppresses the inflammation of nutrient excess
Leila Idrissova1, Harmeet Malhi1, Nathan W Werneburg1
1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States.
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 using 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.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor signaling drives obesity-associated inflammation and metabolic dysfunction. Blocking this pathway prevents weight gain, insulin resistance, and liver damage in mice fed a high-fat diet.
Area of Science:
- Immunology
- Metabolic Syndrome Research
- Molecular Biology
Background:
- Low-grade chronic inflammation is a hallmark of metabolic syndrome.
- The precise mechanisms driving obesity-associated inflammation remain unclear.
Purpose of the Study:
- To investigate the role of TRAIL receptor (TR) signaling in the development of obesity-linked inflammation.
- To utilize genetically modified mice lacking TR to study its function in metabolic disease.
Main Methods:
- TR knockout (TR(-/-)) and wild-type (WT) mice were fed a high-fat, high-cholesterol, high-fructose (FFC) diet or standard chow.
- Metabolic parameters, liver injury, and inflammation in liver and adipose tissues were evaluated.
- Macrophage chemotaxis and activation were assessed in vitro.
Main Results:
- TR deletion completely prevented weight gain, adiposity, and insulin resistance in FFC-fed mice.
- TR(-/-) mice showed suppressed steatohepatitis, with normal liver enzymes and reduced fat accumulation.
- Absence of TR inhibited macrophage accumulation and activation, reducing inflammation in the liver and adipose tissue.
Conclusions:
- Macrophage-associated inflammation in the liver and adipose tissue, driven by nutrient excess, necessitates TR signaling.
- Targeting TR signaling may offer a therapeutic strategy for metabolic syndrome.
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