Abstract
Exosomes are small extracellular membrane vesicles released from endosomes of various cells and could be found in most body fluids. The main functions of exosomes have been recognized as important mediators of intercellular communication and as potential biomarkers of various disease states. This study investigated whether exogenous exosomes from mice with acetaminophen (APAP)-induced liver injury can damage the recipient hepatic cells or promote hepatotoxicity in mice. We observed that exogenous exosomes derived from APAP-exposed mice were internalized into the primary mouse hepatocytes or HepG2 hepatoma cells and significantly decreased the viability of these recipient cells. They also elevated mRNA transcripts and proteins associated with the cell death signaling pathways in primary hepatocytes or HepG2 cells via exosomes-to-cell communications. In addition, confocal microscopy of ex vivo liver section showed that exogenously added exosomes were accumulated in recipient hepatocytes. Furthermore, plasma reactive oxygen species and hepatic TNF-α/IL-1β production were elevated in APAP-exosomes recipient mice compared to control-exosomes recipient mice. The levels of apoptosis-related proteins such as phospho-JNK/JNK, Bax, and cleaved caspase-3 were increased in mouse liver received APAP-exosomes. These results demonstrate that exogenous exosomes from APAP-exposed mice with acute liver injury are functional and stimulate cell death or toxicity of the recipient hepatocytes and mice.
Highlights
Acetaminophen (APAP) is a widely-used analgesic and antipyretic drug with few side effects when used in therapeutic doses[1]
We investigated whether exogenous exosomes containing miRNAs and proteins can regulate the fates of recipient primary hepatocytes or hepatoma cells as well as tissue distribution with hepatic or renal toxicity in living mice
This study first shows that exosomes, released from mice with APAP-induced drug-induced liver injury (DILI), exhibited the functional capacity to communicate with the recipient cells to stimulate the cell death signal with increased phosphorylation and nitrative stress, resulting in decreased cell viability of mouse primary hepatocytes and HepG2 hepatoma cells
Summary
Acetaminophen (APAP) is a widely-used analgesic and antipyretic drug with few side effects when used in therapeutic doses[1]. The main mechanisms of APAP-induced liver injury can be ascribed to both covalent modifications of various protein targets followed by mitochondrial dysfunction and stimulation of the oxidative stress-mediated cell death pathways[6,7]. Exosomes derived from cancer cells can trigger metastasis and promote angiogenesis in recipient cells[24,25] It is poorly understood whether exogenous exosomes derived from mice with APAP-mediated DILI can stimulate cellular toxicity in recipient cells or naïve animals. Based on diverse biological functions of exosomes, we hypothesized that exosomes derived from APAP-exposed mouse liver can promote cellular toxicity and/or activate the apoptosis signals in recipient cells or mice. This work investigated to evaluate whether exogenous exosomes isolated from mice with APAP-induced liver injury can interact with other cells and increase the oxidative stress with stimulation of the apoptosis signaling pathway, resulting in subsequent damage of the recipient cells and mice
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