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HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease.

Publication ,  Journal Article
Chandrashekaran, V; Seth, RK; Dattaroy, D; Alhasson, F; Ziolenka, J; Carson, J; Berger, FG; Kalyanaraman, B; Diehl, AM; Chatterjee, S
Published in: Redox Biol
October 2017

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.

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Published In

Redox Biol

DOI

EISSN

2213-2317

Publication Date

October 2017

Volume

13

Start / End Page

8 / 19

Location

Netherlands

Related Subject Headings

  • Toll-Like Receptor 4
  • Signal Transduction
  • Receptor for Advanced Glycation End Products
  • Rats
  • Peroxynitrous Acid
  • Non-alcoholic Fatty Liver Disease
  • NADPH Oxidases
  • Mice, Inbred C57BL
  • Mice
  • Male
 

Citation

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Chandrashekaran, V., Seth, R. K., Dattaroy, D., Alhasson, F., Ziolenka, J., Carson, J., … Chatterjee, S. (2017). HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease. Redox Biol, 13, 8–19. https://doi.org/10.1016/j.redox.2017.05.005
Chandrashekaran, Varun, Ratanesh K. Seth, Diptadip Dattaroy, Firas Alhasson, Jacek Ziolenka, James Carson, Franklin G. Berger, Balaraman Kalyanaraman, Anna Mae Diehl, and Saurabh Chatterjee. “HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease.Redox Biol 13 (October 2017): 8–19. https://doi.org/10.1016/j.redox.2017.05.005.
Chandrashekaran V, Seth RK, Dattaroy D, Alhasson F, Ziolenka J, Carson J, et al. HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease. Redox Biol. 2017 Oct;13:8–19.
Chandrashekaran, Varun, et al. “HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease.Redox Biol, vol. 13, Oct. 2017, pp. 8–19. Pubmed, doi:10.1016/j.redox.2017.05.005.
Chandrashekaran V, Seth RK, Dattaroy D, Alhasson F, Ziolenka J, Carson J, Berger FG, Kalyanaraman B, Diehl AM, Chatterjee S. HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease. Redox Biol. 2017 Oct;13:8–19.
Journal cover image

Published In

Redox Biol

DOI

EISSN

2213-2317

Publication Date

October 2017

Volume

13

Start / End Page

8 / 19

Location

Netherlands

Related Subject Headings

  • Toll-Like Receptor 4
  • Signal Transduction
  • Receptor for Advanced Glycation End Products
  • Rats
  • Peroxynitrous Acid
  • Non-alcoholic Fatty Liver Disease
  • NADPH Oxidases
  • Mice, Inbred C57BL
  • Mice
  • Male