Open AccessNicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice
Author(s) -
Mukherjee Rajib,
MorenoFernandez Maria E.,
Giles Daniel A.,
Cappelletti Monica,
Stankiewicz Traci E.,
Chan Calvin C.,
Divanovic Senad
Publication year - 2018
Publication title -
hepatology communications
Language(s) - English
Resource type - Journals
ISSN - 2471-254X
DOI - 10.1002/hep4.1162
Subject(s) - nicotinamide adenine dinucleotide phosphate , nonalcoholic fatty liver disease , macrophage polarization , nadph oxidase , endocrinology , medicine , immune system , biology , proinflammatory cytokine , inflammation , cancer research , fatty liver , immunology , oxidase test , macrophage , oxidative stress , biochemistry , disease , in vitro , enzyme
Nonalcoholic fatty liver disease (NAFLD) represents a disease spectrum ranging from benign steatosis to life‐threatening cirrhosis and hepatocellular carcinoma. Elevated levels of reactive oxygen species (ROS) and exacerbated inflammatory responses have been implicated in NAFLD progression. Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 (NOX2; also known as gp91 Phox ), the main catalytic subunit of the nicotinamide adenine dinucleotide phosphate (reduced) oxidase complex, modulates ROS production, immune responsiveness, and pathogenesis of obesity‐associated metabolic derangements. However, the role of NOX2 in the regulation of immune cell function and inflammatory vigor in NAFLD remains underdefined. Here, we demonstrate that obesogenic diet feeding promoted ROS production by bone marrow, white adipose tissue, and liver immune cells. Genetic ablation of NOX2 impeded immune cell ROS synthesis and was sufficient to uncouple obesity from glucose dysmetabolism and NAFLD pathogenesis. Protection from hepatocellular damage in NOX2‐deficient mice correlated with reduced hepatic neutrophil, macrophage, and T‐cell infiltration, diminished production of key NAFLD‐driving proinflammatory cytokines, and an inherent reduction in T‐cell polarization toward Th17 phenotype. Conclusion : Current findings demonstrate a crucial role of the NOX2–ROS axis in immune cell effector function and polarization and consequent NAFLD progression in obesity. Pharmacologic targeting of NOX2 function in immune cells may represent a viable approach for reducing morbidity of obesity‐associated NAFLD pathogenesis. ( Hepatology Communications 2018;2:546‐560)