Malondialdehyde Epitopes Are Sterile Mediators of Hepatic Inflammation in Hypercholesterolemic Mice

Clara Jana-Lui Busch, Tim Hendrikx, David Weismann, Sven Jaeckel, Sofie M. A. Walenbergh, Andre F. Rendeiro, Juliane Weisser, Florian Puhm, Anastasiya Hladik, Laura Goederle, Nikolina Papac-Milicevic, Gerald Haas, Vincent Millischer, Saravanan Subramaniam, Sylvia Knapp, Keiryn L. Bennett, Christoph Bock, Christoph Reinhardt, Ronit Shiri-Sverdlov, Christoph J. Binder*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

30 Citations (Web of Science)

Abstract

Diet-related health issues such as nonalcoholic fatty liver disease and cardiovascular disorders are known to have a major inflammatory component. However, the exact pathways linking diet-induced changes (e. g., hyperlipidemia) and the ensuing inflammation have remained elusive so far. We identified biological processes related to innate immunity and oxidative stress as prime response pathways in livers of low-density lipoprotein receptor-deficient mice on a Western-type diet using RNA sequencing and in silico functional analyses of transcriptome data. The observed changes were independent of the presence of microbiota and thus indicative of a role for sterile triggers. We further show that malondialdehyde (MDA) epitopes, products of lipid peroxidation and markers for enhanced oxidative stress, are detectable in hepatic inflammation predominantly on dying cells and stimulate cytokine secretion as well as leukocyte recruitment in vitro and in vivo. MDA-induced cytokine secretion in vitro was dependent on the presence of the scavenger receptors CD36 and MSR1. Moreover, in vivo neutralization of endogenously generated MDA epitopes by intravenous injection of a specific MDA antibody results in decreased hepatic inflammation in low-density lipoprotein receptor-deficient mice on a Western-type diet. Conclusion: Accumulation of MDA epitopes plays a major role during diet-induced hepatic inflammation and can be ameliorated by administration of an anti-MDA antibody.

Original languageEnglish
Pages (from-to)1181-1195
Number of pages15
JournalHepatology
Volume65
Issue number4
DOIs
Publication statusPublished - Apr 2017

Keywords

  • OXIDATION-SPECIFIC EPITOPES
  • LOW-DENSITY-LIPOPROTEIN
  • FATTY LIVER-DISEASE
  • NONALCOHOLIC STEATOHEPATITIS
  • CARDIOVASCULAR-DISEASE
  • INTESTINAL MICROBIOTA
  • GUT MICROBIOME
  • IGM ANTIBODIES
  • ATHEROSCLEROSIS
  • MACROPHAGES

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