[Inhibition of receptor-interacting protein 3 improves experimental autoimmune hepatitis].

To evaluate the potential of receptor-interacting protein 3 (RIP3) as a therapeutic target for autoimmune hepatitis (AIH). Immunofluorescence assay was used to observe the activated expression levels of RIP3 and its downstream signal mixed lineage protein kinase domain-like protein (MLKL) in the liver tissues of patients with AIH and hepatic cyst. Concanavalin A (ConA) was injected into the tail vein to induce acute immune-mediated hepatitis in mice. Intervention was performed by intraperitoneal injection of RIP3 inhibitor GSK872 or solvent carrier. Peripheral blood and liver tissues were collected. Serum transaminases level, qPCR and flow cytometry were analyzed. The intergroup comparison was performed with an independent sample -test. The expression level of p-RIP3 (the activated forms of RIP3) and phosphorylated p-MLKL (MLKL after phosphorylation) downstream signal were significantly higher in the liver tissue of AIH patients than those of controls. Compared with the control group, the expression levels of RIP3 and MLKL mRNA were significantly increased in the liver tissue of AIH patients (relative expression levels 3.28±0.29 . 0.98±0.09, 4.55±0.51 . 1.06±0.11), and the differences were statistically significant (=6.71 and 6.77, respectively, and <0.01). The expression levels of RIP3 and MLKL mRNA were significantly higher in the mice liver tissue of ConA-induced immune hepatitis than those in the control group (relative expression levels 2.35±0.09 . 0.89±0.11,2.77±0.22 . 0.73±0.16,=10.4,6.33, <0.01). RIP3 inhibitor GSK872 had significantly attenuated ConA-induced immune liver injury and inhibited the expression of tumor necrosis factor-α, interleukin-6, interleukin-1β and NLRP3 in liver. Compared with the control group, the proportions of CD45F4/80 macrophages, CD4 IL-17 Th17 cells, CD4 CD25 regulatory T (Treg) cells and CD11b Gr-1 myeloid derived suppressor cells (MDSCs) were significantly increased in the liver of ConA + Vehicle group. Compared with ConA + Vehicle group, the proportion of CD45F4/80 macrophages and CD4 IL-17 Th17 cells were significantly decreased, while the proportion of CD4 CD25Treg cells and CD11b Gr-1 MDSCs with immunomodulatory functions were significantly increased in mice liver of ConA+GSK872 group. AIH patients and ConA-induced immune hepatitis mice have activated RIP3 signal in liver tissues. Inhibition of RIP3 reduces the expression and proportion of proinflammatory factors and cells, and promotes the accumulation of CD4 CD25 Treg cells and CD11b Gr-1 MDSCs with immunomodulatory functions in the liver of mice with immune hepatitis, thereby alleviating liver inflammation and injury. Therefore, the inhibition of RIP3 is expected to be a new approach for the treatment of AIH.