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

Redox Biol. 2017 Oct;13:8-19. doi: 10.1016/j.redox.2017.05.005. Epub 2017 May 10.

Abstract

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.

Keywords: DAMP; FBA; Flotillin; NADPH oxidase; Nonalcoholic steatohepatitis; TLR4.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Cytokines / metabolism
  • Enterocytes / metabolism
  • HMGB1 Protein / metabolism*
  • Inflammatory Bowel Diseases / etiology
  • Inflammatory Bowel Diseases / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NADPH Oxidases / metabolism
  • Non-alcoholic Fatty Liver Disease / complications
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Peroxynitrous Acid / metabolism*
  • Rats
  • Receptor for Advanced Glycation End Products / metabolism*
  • Signal Transduction*
  • Toll-Like Receptor 4 / metabolism

Substances

  • Cytokines
  • HMGB1 Protein
  • HMGB1 protein, mouse
  • Receptor for Advanced Glycation End Products
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Peroxynitrous Acid
  • NADPH Oxidases