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Objective To explore the protective effect of exosomes derived from M2 macrophages (M2 Exos) on concanavalin (Con) A induced autoimmune hepatitis in mice. Methods RAW264.7 macrophages were treated with IL-4 (20 μg/L) for 24 h to obtain cell culture supernatant containing M2 Exos. M2 Exos were separated by ultracentrifugation and identified by transmission electron microscope, nanoparticle tracking analysis and Western blot assay. Immunofluorescence was used to detect whether M2 Exos were uptaken by RAW264.7 macrophages. Twelve C57BL/6J mice were randomly divided into PBS group, DiR-M0 Exos group, DiR-M2 Exos group and DiR dye control group. PBS solution, DiR-M0 Exos (100 μg), DiR-M2 Exos (100 μg) and DiR dye were given to corresponding groups through tail veins after the injection of Con A (15 mg/kg) for 1h. The distribution of Exos in liver, spleen, heart, lung, kidney and intestine of mice with autoimmune hepatitis was observed by vivo imaging system. Twenty C57BL/6J mice were randomly divided into control group (PBS solution), Con A group (15 mg/kg Con A), M0 Exos group (15 mg/kg Con A + 200 μg M0 Exos) and M2 Exos group (15 mg/kg Con A+200 μg M0 Exos), 5 mice in each group. Peripheral blood and liver tissues were collected 12 h after Con A injection. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined by automated biochemistry analyzer. The histological profiles of liver tissue were observed by hematoxylin-eosin (HE) staining. The mRNA expression levels of liver TNF-α and IL-6 were detected with quantitative real-time PCR (qPCR). The changes of liver macrophage subpopulations were detected with flow cytometric analysis. Results M2 Exos were successfully induced and isolated, which can be taken up by RAW264.7 macrophages in large quantities. M2 Exos were mainly absorbed by liver and spleen of mice through tail vein injection. Compared with Control group, the serum levels of ALT and AST were significantly increased in Con A group (both P＜0.05). The disordered liver structure and increased necrosis areas were found in Con A group. Meanwhile, the mRNA expression of TNF- α and IL-6 in liver increased (both P＜0.05). The infiltration of liver monocyte-derived macrophages (MoMFs) increased (P＜0.05). Compared with Con A group, the serum levels of ALT and AST were significantly decreased in M2 Exos group (both P＜0.05). M2 Exos group also showed lower liver TNF-α, IL-6 mRNA expression levels (both P＜0.05) and lower MoMFs infiltration. HE staining showed that the necrosis areas of liver cells were relieved in M2 Exos group. Conclusion M2 Exos plays a protective role in autoimmune hepatitis in model mice，and its mechanism may be related to the decreased production of liver inflammatory cytokines and decreased recruitment of MoMFs. [ABSTRACT FROM AUTHOR]