Myeloid-derived suppressor cells ameliorate liver mitochondrial damage to protect against autoimmune hepatitis by releasing small extracellular vesicles.

ABSTRACT

BACKGROUND: Autoimmune hepatitis (AIH) is an inflammatory liver disease that is associated with impaired self-tolerance. Myeloid-derived supprfessor cells (MDSCs) have been considered to exert counterregulatory effects on AIH. However, the specific mechanism underlying these effects is unclear. Herein, we investigated the efficacy and safety of MDSCs in protecting against AIH and explored the underlying mechanism. METHODS: Circulating and liver MDSC expression levels in 71 AIH patients and 47 healthy control (HC) individuals were detected by flow cytometry and immunohistochemistry. The adoptive transfer of induced bone marrow-derived MDSCs (BM MDSCs) to AIH mice was used to explore the function of MDSCs. Hepatic injury and mitochondrial damage were evaluated by transaminase levels, histopathology, immunohistochemistry, transmission electron microscopy and western blotting. MDSCs were pretreated with the small extracellular vesicle (sEV) generation inhibitor GW4869 to explore the mechanism. Importantly, sEVs derived from MDSCs and MDSCs-GW4869 were injected into model mice to monitor mitochondrial function and biogenesis. RESULTS: Circulating and liver MDSCs were expanded in AIH patients and mouse model. Furthermore, the follow-up data of AIH patients showed that immunosuppressive therapy further promoted the expansion of MDSCs. More importantly, the adoptive transfer of BM MDSCs to AIH mice effectively ameliorated liver injury and regulated the imbalance of the immune microenvironment. Additionally, BM MDSCs reduced liver mitochondrial damage and improved mitochondrial biogenesis. Mechanistically, sEVs derived from BM MDSCs showed the same biological effects as cells, and blocking sEV production weakened the function of BM MDSCs. Finally, multiple long-term administrations of BM MDSCs were proven to be safe in general. CONCLUSION: In conclusion, MDSCs ameliorate liver mitochondrial damage to protect against autoimmune hepatitis by releasing small extracellular vesicles.