title: NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation.
abstract: Metabolic reprogramming is implicated in macrophage activation, but the underlying mechanisms are poorly understood. Here, we demonstrate that the NOTCH1 pathway dictates activation of M1 phenotypes in isolated mouse hepatic macrophages (HMacs) and in a murine macrophage cell line by coupling transcriptional upregulation of M1 genes with metabolic upregulation of mitochondrial oxidative phosphorylation and ROS (mtROS) to augment induction of M1 genes. Enhanced mitochondrial glucose oxidation was achieved by increased recruitment of the NOTCH1 intracellular domain (NICD1) to nuclear and mitochondrial genes that encode respiratory chain components and by NOTCH-dependent induction of pyruvate dehydrogenase phosphatase 1 (Pdp1) expression, pyruvate dehydrogenase activity, and glucose flux to the TCA cycle. As such, inhibition of the NOTCH pathway or Pdp1 knockdown abrogated glucose oxidation, mtROS, and M1 gene expression. Conditional NOTCH1 deficiency in the myeloid lineage attenuated HMac M1 activation and inflammation in a murine model of alcoholic steatohepatitis and markedly reduced lethality following endotoxin-mediated fulminant hepatitis in mice. In vivo monocyte tracking further demonstrated the requirement of NOTCH1 for the migration of blood monocytes into the liver and subsequent M1 differentiation. Together, these results reveal that NOTCH1 promotes reprogramming of mitochondrial metabolism for M1 macrophage activation.
authors: Jun
authors: J
authors: Xu
authors: Feng
authors: F
authors: Chi
authors: Tongsheng
authors: T
authors: Guo
authors: Vasu
authors: V
authors: Punj
authors: W N Paul
authors: WN
authors: Lee
authors: Samuel W
authors: SW
authors: French
authors: Hidekazu
authors: H
authors: Tsukamoto
mesh_terms: D000818:Animals; D002460:Cell Line; D004579:Electron Transport / Q000235:genetics; D019446:Endotoxemia / Q000150:complications; D005235:Fatty Liver, Alcoholic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D017114:Liver Failure, Acute / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D010085:Oxidative Phosphorylation; D017434:Protein Structure, Tertiary; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051881:Receptor, Notch1 / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: C497762:Notch1 protein, mouse; D011768:Pyruvate Dehydrogenase Complex; D017382:Reactive Oxygen Species; D051881:Receptor, Notch1; D009569:Nitric Oxide; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase; D005947:Glucose