zVAD alleviates experimental autoimmune hepatitis in mice by increasing the sensitivity of macrophage to TNFR1-dependent necroptosis

被引:18
作者
Li, Xuehui [1 ]
Zhang, Yongting [1 ]
Wang, Jinping [3 ]
Li, Yuyu [1 ]
Wang, Yuchong [1 ]
Shi, Fan [1 ]
Hong, Liang [1 ]
Li, Lanjuan [1 ,2 ]
Diao, Hongyan [1 ]
机构
[1] Zhejiang Univ, Affiliated Hosp 1, Natl Clin Res Ctr Infect Dis, Sch Med,Natl Med Ctr Infect Dis,Collaborat Innovat, Hangzhou, Peoples R China
[2] Jinan Microecol Biomed Shandong Lab, Jinan, Peoples R China
[3] Wenzhou Med Univ, Sch Lab Med & Life Sci, Wenzhou, Peoples R China
关键词
Liver injury; zVAD; Macrophages; Necroptosis; TNFR1; LIVER; INFLAMMATION; OSTEOPONTIN; CELL; TNF; EXPRESSION; INHIBITORS; FIBROSIS; NECROSIS; INJURY;
D O I
10.1016/j.jaut.2022.102904
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background & aims: Autoimmune hepatitis (AIH) is characterized by hepatocyte destruction, leading to lymphocyte and macrophage accumulation in the liver. Macrophages are key drivers of AIH. A membranepermeable pan-caspase inhibitor, Z-Val-Ala-DL-Asp-fluoromethylketone (zVAD), induces macrophage necroptosis in response to certain stimuli. However, the function of zVAD in the pathogenesis of autoimmune hepatitis remains elusive. In this study, we aimed to evaluate the effect and explore the underlying mechanisms of zVAD against AIH.Methods: Murine acute autoimmune liver injury was established by concanavalin A (ConA) injection. Bone marrow-derived macrophages (BMDMs) were used in adoptive cell transfer experiments. The mechanism of action of zVAD was examined using macrophage cell lines and BMDMs. Phosphorylation of mixed lineage kinase domain-like proteins was used as a marker of necroptosis.Results: Treatment with zVAD increased necroptosis, reduced inflammatory cytokine production, and alleviated liver injury in a ConA-induced liver injury mouse model. Regardless of zVAD treatment, macrophage deletion resulted in reduced neutrophil accumulation and relieved ConA-induced liver injury. In vitro studies have shown that zVAD pretreatment promotes lipopolysaccharide-induced macrophage necroptosis and leads to reduced proinflammatory cytokine and chemokine secretion. Transferring zVAD-pretreated BMDMs in mice notably reduced ConA-associated liver inflammation and injury, resulting in lower mortality than that observed after transferring normal BMDMs. Mechanistically, zVAD treatment increased the expression of tumour necrosis factor receptor (TNFR)-1 and interleukin (IL)-10 in macrophages. TNFR1 expression decreased upon transfection with IL-10specific small interfering RNAs and blocking of TNFR1 decreased macrophage necroptosis.Conclusions: We found that zVAD alleviated ConA-induced liver injury by increasing the sensitivity of macrophages to necroptosis via IL-10-induced TNFR1 expression. This study provides new insights into the treatment of autoimmune hepatitis via zVAD-induced macrophage necroptosis.
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页数:14
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