title: Immune activation resulting from NKG2D/ligand interaction promotes atherosclerosis.
abstract: BACKGROUND
  The interplay between the immune system and abnormal metabolic conditions sustains and propagates a vicious feedback cycle of chronic inflammation and metabolic dysfunction that is critical for atherosclerotic progression. It is well established that abnormal metabolic conditions, such as dyslipidemia and hyperglycemia, cause various cellular stress responses that induce tissue inflammation and immune cell activation, which in turn exacerbate the metabolic dysfunction. However, molecular events linking these processes are not well understood.
  
  
  RESULTS
  Tissues and organs of humans and mice with hyperglycemia and hyperlipidemia were examined for expression of ligands for NKG2D, a potent immune-activating receptor expressed by several types of immune cells, and the role of NKG2D in atherosclerosis and metabolic diseases was probed with the use of mice lacking NKG2D or by blocking NKG2D with monoclonal antibodies. NKG2D ligands were upregulated in multiple organs, particularly atherosclerotic aortas and inflamed livers. Ligand upregulation was induced in vitro by abnormal metabolites associated with metabolic dysfunctions. Using apolipoprotein E-deficient mouse models, we demonstrated that preventing NKG2D functions resulted in a dramatic reduction in plaque formation, suppressed systemic and organ inflammation mediated by multiple immune cell types, and alleviated abnormal metabolic conditions.
  
  
  CONCLUSIONS
  The NKG2D/ligand interaction is a critical molecular link in the vicious cycle of chronic inflammation and metabolic dysfunction that promotes atherosclerosis and might be a useful target for therapeutic intervention in the disease.
authors: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, 115 Henning Bldg, University Park, PA 16802, USA.
authors: Mingcan
authors: M
authors: Xia
authors: Nadia
authors: N
authors: Guerra
authors: Galina K
authors: GK
authors: Sukhova
authors: Kangkang
authors: K
authors: Yang
authors: Carla K
authors: CK
authors: Miller
authors: Guo-Ping
authors: GP
authors: Shi
authors: David H
authors: DH
authors: Raulet
authors: Na
authors: N
authors: Xiong
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000378:metabolism; D006505:Hepatitis / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000276:immunology; D008024:Ligands; D008297:Male; D024821:Metabolic Syndrome / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D015415:Biomarkers; D016207:Cytokines; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K