Extracellular vesicles released by polycyclic aromatic hydrocarbons-treated hepatocytes trigger oxidative stress in recipient hepatocytes by delivering iron

Nettie van Meteren (1) , Dominique Lagadic-Gossmann (1) , Normand Podechard (1) , Dimitri Gobart (1) , Isabelle Gallais (1) , Martine Chevanne (1) , Aurore Collin (1) , Agnès Burel (2) , Aurélien Dupont (2) , Ludivine Rault (3) , Soizic Chevance (4) , Fabienne Gauffre (4) , Eric Le Ferrec (1) , Odile Sergent (1)

1 Irset - Institut de recherche en santé, environnement et travail
2 SFR UMS CNRS 3480 - INSERM 018 - Biosit : biologie, santé, innovation technologique
3 ScanMAT - Synthèse Caractérisation Analyse de la Matière
4 ISCR - Institut des Sciences Chimiques de Rennes

A growing body of evidences indicate the major role of extracellular vesicles (EVs) as players of cell communication in the pathogenesis of liver diseases. EVs are membrane-enclosed vesicles released by cells into the extracellular environment. Oxidative stress is also a key component of liver disease pathogenesis, but no role for hepatocyte-derived EVs has yet been described in the development of this process. Recently, some polycyclic aromatic hydrocarbons (PAHs), widespread environmental contaminants, were demonstrated to induce EV release from hepatocytes. They are also well-known to trigger oxidative stress leading to cell death. Therefore, the aim of this work was to investigate the involvement of EVs derived from PAHs-treated hepatocytes (PAH-EVs) in possible oxidative damages of healthy recipient hepatocytes, using both WIF-B9 and primary rat hepatocytes. We first showed that the release of EVs from PAHs -treated hepatocytes depended on oxidative stress. PAH-EVs were enriched in proteins related to oxidative stress such as NADPH oxidase and ferritin. They were also demonstrated to contain more iron. PAH-EVs could then induce oxidative stress in recipient hepatocytes, thereby leading to apoptosis. Mitochondria and lysosomes of recipient hepatocytes exhibited significant structural alterations. All those damages were dependent on internalization of EVs that reached lysosomes with their cargoes. Lysosomes thus appeared as critical organelles for EVs to induce apoptosis. In addition, pro-oxidant components of PAH-EVs, e.g. NADPH oxidase and iron, were revealed to be necessary for this cell death.

Mots clés: Extracellular vesicles; Ferritin; Hepatocytes; LMW iron; Lipid peroxidation; Lysosomes; Mitochondria; NADPH oxidase; Polycyclic aromatic hydrocarbons

Domaines: Sciences du Vivant [q-bio]

Nettie van Meteren, Dominique Lagadic-Gossmann, Normand Podechard, Dimitri Gobart, Isabelle Gallais, et al.. Extracellular vesicles released by polycyclic aromatic hydrocarbons-treated hepatocytes trigger oxidative stress in recipient hepatocytes by delivering iron. Free Radical Biology and Medicine, 2020, 160, pp.246-262. ⟨10.1016/j.freeradbiomed.2020.08.001⟩. ⟨hal-02930146⟩