ABSTRACT
The simultaneous abuse of alcohol-cocaine is known to cause stronger and more unpredictable cellular damage in the liver, heart, and brain. However, the mechanistic crosstalk between cocaine and alcohol in liver injury remains unclear. The findings revealed cocaine-induced liver injury and inflammation in both marmosets and mice. Of note, co-administration of cocaine and ethanol in mice causes more severe liver damage than individual treatment. The metabolomic analysis confirmed that hippuric acid (HA) is the most abundant metabolite in marmoset serum after cocaine consumption and that is formed in primary marmoset hepatocytes. HA, a metabolite of cocaine, increases mitochondrial DNA leakage and subsequently increases the production of proinflammatory factors via STING signaling in Kupffer cells (KCs). In addition, conditioned media of cocaine-treated KC induced hepatocellular necrosis via alcohol-induced TNFR1. Finally, disruption of STING signaling in vivo ameliorated co-administration of alcohol- and cocaine-induced liver damage and inflammation. These findings postulate intervention of HA-STING-TNFR1 axis as a novel strategy for treatment of alcohol- and cocaine-induced excessive liver damage.
Subject(s)
Cocaine , DNA, Mitochondrial , Hippurates , Liver Diseases, Alcoholic , Membrane Proteins , Signal Transduction , Animals , Cocaine/pharmacology , Cocaine/toxicity , Signal Transduction/drug effects , Liver Diseases, Alcoholic/metabolism , Liver Diseases, Alcoholic/pathology , DNA, Mitochondrial/metabolism , DNA, Mitochondrial/drug effects , Mice , Hippurates/metabolism , Male , Membrane Proteins/metabolism , Hepatocytes/metabolism , Hepatocytes/drug effects , Kupffer Cells/drug effects , Kupffer Cells/metabolism , Liver/drug effects , Liver/metabolism , Liver/pathology , Ethanol/toxicity , Mice, Inbred C57BL , Cocaine-Related Disorders/metabolism , Receptors, Tumor Necrosis Factor, Type I/metabolismABSTRACT
Mitochondria play a central role in the pathophysiology of inflammatory bowel disease (IBD) and colorectal cancer (CRC). The maintenance of mitochondrial function is necessary for a stable immune system. Mitochondrial dysfunction in the gastrointestinal system leads to the excessive activation of multiple inflammatory signaling pathways, leading to IBD and increased severity of CRC. In this review, we focus on the mitochondria and inflammatory signaling pathways and its related gastrointestinal diseases.