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

Varun Chandrashekaran, Ratanesh K. Seth, Diptadip Dattaroy, Firas Alhasson, Jacek Ziolenka, James Carson, Franklin G. Berger, Balaraman Kalyanaraman, Anna Mae Diehl, Saurabh Chatterjee

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)8-19
Number of pages12
JournalRedox Biology
Volume13
DOIs
StatePublished - Oct 1 2017

Fingerprint

Peroxynitrous Acid
NADPH Oxidase
Inflammatory Bowel Diseases
Liver
Inflammation
Chemical activation
Cytokines
Toll-Like Receptor 4
Oxidation-Reduction
Boronic Acids
HMGB1 Protein
Inflammation Mediators
Nitration
Advanced Glycosylation End Product-Specific Receptor
Non-alcoholic Fatty Liver Disease
Pathology
Intestines
Tyrosine
Epithelial Cells
Phenotype

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Organic Chemistry

Cite this

HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease. / Chandrashekaran, Varun; Seth, Ratanesh K.; Dattaroy, Diptadip; Alhasson, Firas; Ziolenka, Jacek; Carson, James; Berger, Franklin G.; Kalyanaraman, Balaraman; Diehl, Anna Mae; Chatterjee, Saurabh.

In: Redox Biology, Vol. 13, 01.10.2017, p. 8-19.

Research output: Contribution to journalArticle

Chandrashekaran, V, Seth, RK, Dattaroy, D, Alhasson, F, Ziolenka, J, Carson, J, Berger, FG, Kalyanaraman, B, Diehl, AM & Chatterjee, S 2017, 'HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease', Redox Biology, vol. 13, pp. 8-19. https://doi.org/10.1016/j.redox.2017.05.005
Chandrashekaran, Varun ; Seth, Ratanesh K. ; Dattaroy, Diptadip ; Alhasson, Firas ; Ziolenka, Jacek ; Carson, James ; Berger, Franklin G. ; Kalyanaraman, Balaraman ; Diehl, Anna Mae ; Chatterjee, Saurabh. / HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease. In: Redox Biology. 2017 ; Vol. 13. pp. 8-19.
@article{0a5a75a2c36f48b5b08d4a2781f67659,
title = "HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease",
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.",
author = "Varun Chandrashekaran and Seth, {Ratanesh K.} and Diptadip Dattaroy and Firas Alhasson and Jacek Ziolenka and James Carson and Berger, {Franklin G.} and Balaraman Kalyanaraman and Diehl, {Anna Mae} and Saurabh Chatterjee",
year = "2017",
month = "10",
day = "1",
doi = "10.1016/j.redox.2017.05.005",
language = "English (US)",
volume = "13",
pages = "8--19",
journal = "Redox Biology",
issn = "2213-2317",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease

AU - Chandrashekaran, Varun

AU - Seth, Ratanesh K.

AU - Dattaroy, Diptadip

AU - Alhasson, Firas

AU - Ziolenka, Jacek

AU - Carson, James

AU - Berger, Franklin G.

AU - Kalyanaraman, Balaraman

AU - Diehl, Anna Mae

AU - Chatterjee, Saurabh

PY - 2017/10/1

Y1 - 2017/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85019958332&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019958332&partnerID=8YFLogxK

U2 - 10.1016/j.redox.2017.05.005

DO - 10.1016/j.redox.2017.05.005

M3 - Article

VL - 13

SP - 8

EP - 19

JO - Redox Biology

JF - Redox Biology

SN - 2213-2317

ER -