HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease
Recent clinical studies found a strong association of colonic inflammation and Inflammatory bowel disease (IBD)-like phenotype with NonAlcoholic Fatty liver Disease (NAFLD) yet the mechanisms remain unknown. The present study identifies high mobility group box 1 (HMGB1) as a key mediator of intestin...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2017-10-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231717302744 |
| _version_ | 1811285289097756672 |
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| author | Varun Chandrashekaran Ratanesh K. Seth Diptadip Dattaroy Firas Alhasson Jacek Ziolenka James Carson Franklin G. Berger Balaraman Kalyanaraman Anna Mae Diehl Saurabh Chatterjee |
| author_facet | Varun Chandrashekaran Ratanesh K. Seth Diptadip Dattaroy Firas Alhasson Jacek Ziolenka James Carson Franklin G. Berger Balaraman Kalyanaraman Anna Mae Diehl Saurabh Chatterjee |
| author_sort | Varun Chandrashekaran |
| collection | DOAJ |
| description | Recent clinical studies found a strong association of colonic inflammation and Inflammatory bowel disease (IBD)-like phenotype with NonAlcoholic Fatty liver Disease (NAFLD) yet the mechanisms remain unknown. The present study identifies high mobility group box 1 (HMGB1) as a key mediator of intestinal inflammation in NAFLD and outlines a detailed redox signaling mechanism for such a pathway. NAFLD mice showed liver damage and release of elevated HMGB1 in systemic circulation and increased intestinal tyrosine nitration that was dependent on NADPH oxidase. Intestines from NAFLD mice showed higher Toll like receptor 4 (TLR4) activation and proinflammatory cytokine release, an outcome strongly dependent on the existence of NAFLD pathology and NADPH oxidase. Mechanistically intestinal epithelial cells showed the HMGB1 activation of TLR-4 was both NADPH oxidase and peroxynitrite dependent with the latter being formed by the activation of NADPH oxidase. Proinflammatory cytokine production was significantly blocked by the specific peroxynitrite scavenger phenyl boronic acid (FBA), AKT inhibition and NADPH oxidase inhibitor Apocynin suggesting NADPH oxidase-dependent peroxynitrite is a key mediator in TLR-4 activation and cytokine release via an AKT dependent pathway. Studies to ascertain the mechanism of HMGB1-mediated NADPH oxidase activation showed a distinct role of Receptor for advanced glycation end products (RAGE) as the use of inhibitors targeted against RAGE or use of deformed HMGB1 protein prevented NADPH oxidase activation, peroxynitrite formation, TLR4 activation and finally cytokine release. Thus, in conclusion the present study identifies a novel role of HMGB1 mediated inflammatory pathway that is RAGE and redox signaling dependent and helps promote ectopic intestinal inflammation in NAFLD. |
| first_indexed | 2024-04-13T02:41:53Z |
| format | Article |
| id | doaj.art-24e8fd36be8c4ea0a6d7358176b07182 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-13T02:41:53Z |
| publishDate | 2017-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-24e8fd36be8c4ea0a6d7358176b071822022-12-22T03:06:10ZengElsevierRedox Biology2213-23172017-10-0113C81910.1016/j.redox.2017.05.005HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver diseaseVarun Chandrashekaran0Ratanesh K. Seth1Diptadip Dattaroy2Firas Alhasson3Jacek Ziolenka4James Carson5Franklin G. Berger6Balaraman Kalyanaraman7Anna Mae Diehl8Saurabh Chatterjee9Environmental Health and Disease Laboratory, Departments of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208, USAEnvironmental Health and Disease Laboratory, Departments of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208, USAEnvironmental Health and Disease Laboratory, Departments of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208, USAEnvironmental Health and Disease Laboratory, Departments of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208, USAFree Radical Research Center, Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USAExercise Science, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USADepartment of Biological Sciences and Center for Colon Cancer Research, University of South Carolina, SC 29208, USAFree Radical Research Center, Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USADivision of Gastroenterology, Duke University, Durham, NC 27707, USAEnvironmental Health and Disease Laboratory, Departments of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208, USARecent clinical studies found a strong association of colonic inflammation and Inflammatory bowel disease (IBD)-like phenotype with NonAlcoholic Fatty liver Disease (NAFLD) yet the mechanisms remain unknown. The present study identifies high mobility group box 1 (HMGB1) as a key mediator of intestinal inflammation in NAFLD and outlines a detailed redox signaling mechanism for such a pathway. NAFLD mice showed liver damage and release of elevated HMGB1 in systemic circulation and increased intestinal tyrosine nitration that was dependent on NADPH oxidase. Intestines from NAFLD mice showed higher Toll like receptor 4 (TLR4) activation and proinflammatory cytokine release, an outcome strongly dependent on the existence of NAFLD pathology and NADPH oxidase. Mechanistically intestinal epithelial cells showed the HMGB1 activation of TLR-4 was both NADPH oxidase and peroxynitrite dependent with the latter being formed by the activation of NADPH oxidase. Proinflammatory cytokine production was significantly blocked by the specific peroxynitrite scavenger phenyl boronic acid (FBA), AKT inhibition and NADPH oxidase inhibitor Apocynin suggesting NADPH oxidase-dependent peroxynitrite is a key mediator in TLR-4 activation and cytokine release via an AKT dependent pathway. Studies to ascertain the mechanism of HMGB1-mediated NADPH oxidase activation showed a distinct role of Receptor for advanced glycation end products (RAGE) as the use of inhibitors targeted against RAGE or use of deformed HMGB1 protein prevented NADPH oxidase activation, peroxynitrite formation, TLR4 activation and finally cytokine release. Thus, in conclusion the present study identifies a novel role of HMGB1 mediated inflammatory pathway that is RAGE and redox signaling dependent and helps promote ectopic intestinal inflammation in NAFLD.http://www.sciencedirect.com/science/article/pii/S2213231717302744Nonalcoholic steatohepatitisDAMPFBATLR4FlotillinNADPH oxidase |
| spellingShingle | Varun Chandrashekaran Ratanesh K. Seth Diptadip Dattaroy Firas Alhasson Jacek Ziolenka James Carson Franklin G. Berger Balaraman Kalyanaraman Anna Mae Diehl Saurabh Chatterjee HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease Redox Biology Nonalcoholic steatohepatitis DAMP FBA TLR4 Flotillin NADPH oxidase |
| title | HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease |
| title_full | HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease |
| title_fullStr | HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease |
| title_full_unstemmed | HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease |
| title_short | HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease |
| title_sort | hmgb1 rage pathway drives peroxynitrite signaling induced ibd like inflammation in murine nonalcoholic fatty liver disease |
| topic | Nonalcoholic steatohepatitis DAMP FBA TLR4 Flotillin NADPH oxidase |
| url | http://www.sciencedirect.com/science/article/pii/S2213231717302744 |
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