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Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice
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. Nicotina...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944572/ https://www.ncbi.nlm.nih.gov/pubmed/29761170 http://dx.doi.org/10.1002/hep4.1162 |
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author | Mukherjee, Rajib Moreno‐Fernandez, Maria E. Giles, Daniel A. Cappelletti, Monica Stankiewicz, Traci E. Chan, Calvin C. Divanovic, Senad |
author_facet | Mukherjee, Rajib Moreno‐Fernandez, Maria E. Giles, Daniel A. Cappelletti, Monica Stankiewicz, Traci E. Chan, Calvin C. Divanovic, Senad |
author_sort | Mukherjee, Rajib |
collection | PubMed |
description | 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) |
format | Online Article Text |
id | pubmed-5944572 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-59445722018-05-14 Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice Mukherjee, Rajib Moreno‐Fernandez, Maria E. Giles, Daniel A. Cappelletti, Monica Stankiewicz, Traci E. Chan, Calvin C. Divanovic, Senad Hepatol Commun Original Articles 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) John Wiley and Sons Inc. 2018-03-24 /pmc/articles/PMC5944572/ /pubmed/29761170 http://dx.doi.org/10.1002/hep4.1162 Text en © 2018 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Mukherjee, Rajib Moreno‐Fernandez, Maria E. Giles, Daniel A. Cappelletti, Monica Stankiewicz, Traci E. Chan, Calvin C. Divanovic, Senad Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice |
title | Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice |
title_full | Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice |
title_fullStr | Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice |
title_full_unstemmed | Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice |
title_short | Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice |
title_sort | nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944572/ https://www.ncbi.nlm.nih.gov/pubmed/29761170 http://dx.doi.org/10.1002/hep4.1162 |
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