STING-IRF3 Triggers Endothelial Inflammation in Response to Free Fatty Acid-Induced Mitochondrial Damage in Diet-Induced Obesity

Arterioscler Thromb Vasc Biol. 2017 May;37(5):920-929. doi: 10.1161/ATVBAHA.117.309017. Epub 2017 Mar 16.


Objective: Metabolic stress in obesity induces endothelial inflammation and activation, which initiates adipose tissue inflammation, insulin resistance, and cardiovascular diseases. However, the mechanisms underlying endothelial inflammation induction are not completely understood. Stimulator of interferon genes (STING) is an important molecule in immunity and inflammation. In the present study, we sought to determine the role of STING in palmitic acid-induced endothelial activation/inflammation.

Approach and results: In cultured endothelial cells, palmitic acid treatment activated STING, as indicated by its perinuclear translocation and binding to interferon regulatory factor 3 (IRF3), leading to IRF3 phosphorylation and nuclear translocation. The activated IRF3 bound to the promoter of ICAM-1 (intercellular adhesion molecule 1) and induced ICAM-1 expression and monocyte-endothelial cell adhesion. When analyzing the upstream signaling, we found that palmitic acid activated STING by inducing mitochondrial damage. Palmitic acid treatment caused mitochondrial damage and leakage of mitochondrial DNA into the cytosol. Through the cytosolic DNA sensor cGAS (cyclic GMP-AMP synthase), the mitochondrial damage and leaked cytosolic mitochondrial DNA activated the STING-IRF3 pathway and increased ICAM-1 expression. In mice with diet-induced obesity, the STING-IRF3 pathway was activated in adipose tissue. However, STING deficiency (Stinggt/gt ) partially prevented diet-induced adipose tissue inflammation, obesity, insulin resistance, and glucose intolerance.

Conclusions: The mitochondrial damage-cGAS-STING-IRF3 pathway is critically involved in metabolic stress-induced endothelial inflammation. STING may be a potential therapeutic target for preventing cardiovascular diseases and insulin resistance in obese individuals.

Keywords: DNA, mitochondrial; diet, high-fat; endothelium; palmitic acid; vascular diseases.

MeSH terms

  • Active Transport, Cell Nucleus
  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Adipose Tissue / pathology
  • Animals
  • Cell Line, Tumor
  • Coculture Techniques
  • DNA, Mitochondrial / metabolism
  • Diet, High-Fat*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Inflammation / prevention & control
  • Insulin Resistance
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism*
  • Male
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Nucleotidyltransferases / metabolism
  • Obesity / genetics
  • Obesity / metabolism*
  • Obesity / pathology
  • Palmitic Acid / pharmacology*
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Binding
  • RNA Interference
  • Signal Transduction
  • Transfection


  • DNA, Mitochondrial
  • ICAM1 protein, human
  • IRF3 protein, human
  • Icam1 protein, mouse
  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • Membrane Proteins
  • STING1 protein, human
  • Sting1 protein, mouse
  • Intercellular Adhesion Molecule-1
  • Palmitic Acid
  • Nucleotidyltransferases
  • cGAS protein, human