NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation

Area of Science:

• Immunology
• Cell Biology
• Metabolic pathways

Background:

• Macrophage activation, particularly M1 polarization, is vital in immunity but its metabolic underpinnings remain unclear.
• Metabolic reprogramming is a hallmark of activated macrophages, yet the specific pathways controlling this process are not fully elucidated.

Purpose of the Study:

• To investigate the role of the NOTCH1 pathway in regulating M1 macrophage activation and associated metabolic changes.
• To elucidate the molecular mechanisms by which NOTCH1 influences macrophage metabolism and function.

Main Methods:

• Utilized isolated mouse hepatic macrophages (HMacs) and a murine macrophage cell line.
• Investigated NOTCH1 signaling, mitochondrial oxidative phosphorylation, reactive oxygen species (ROS) production, and gene expression.
• Employed Pdp1 knockdown and conditional NOTCH1 deficiency models in mice.
• Tracked monocyte migration in vivo.

Main Results:

• NOTCH1 signaling upregulates M1 genes and enhances mitochondrial oxidative phosphorylation and mitochondrial ROS (mtROS) production.
• NOTCH1 promotes glucose oxidation via increased NICD1 recruitment to metabolic genes and induction of Pdp1.
• Inhibition of NOTCH1 or Pdp1 abrogated M1 activation, glucose oxidation, and mtROS.
• Conditional NOTCH1 deficiency reduced M1 activation and liver inflammation in alcoholic steatohepatitis models and decreased mortality in fulminant hepatitis models.
• NOTCH1 is essential for monocyte recruitment to the liver and subsequent M1 differentiation.

Conclusions:

• The NOTCH1 pathway is a key regulator of M1 macrophage activation by orchestrating metabolic reprogramming, specifically enhancing mitochondrial glucose oxidation and mtROS production.
• NOTCH1 signaling is critical for hepatic macrophage activation, inflammation, and monocyte differentiation in vivo.
• Targeting the NOTCH1 pathway may offer therapeutic strategies for inflammatory liver diseases.