TY - JOUR
T1 - Malondialdehyde Epitopes Are Sterile Mediators of Hepatic Inflammation in Hypercholesterolemic Mice
AU - Busch, Clara Jana-Lui
AU - Hendrikx, Tim
AU - Weismann, David
AU - Jaeckel, Sven
AU - Walenbergh, Sofie M. A.
AU - Rendeiro, Andre F.
AU - Weisser, Juliane
AU - Puhm, Florian
AU - Hladik, Anastasiya
AU - Goederle, Laura
AU - Papac-Milicevic, Nikolina
AU - Haas, Gerald
AU - Millischer, Vincent
AU - Subramaniam, Saravanan
AU - Knapp, Sylvia
AU - Bennett, Keiryn L.
AU - Bock, Christoph
AU - Reinhardt, Christoph
AU - Shiri-Sverdlov, Ronit
AU - Binder, Christoph J.
PY - 2017/4
Y1 - 2017/4
N2 - 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.
AB - 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.
KW - OXIDATION-SPECIFIC EPITOPES
KW - LOW-DENSITY-LIPOPROTEIN
KW - FATTY LIVER-DISEASE
KW - NONALCOHOLIC STEATOHEPATITIS
KW - CARDIOVASCULAR-DISEASE
KW - INTESTINAL MICROBIOTA
KW - GUT MICROBIOME
KW - IGM ANTIBODIES
KW - ATHEROSCLEROSIS
KW - MACROPHAGES
U2 - 10.1002/hep.28970
DO - 10.1002/hep.28970
M3 - Article
C2 - 27981604
SN - 0270-9139
VL - 65
SP - 1181
EP - 1195
JO - Hepatology
JF - Hepatology
IS - 4
ER -