PMID- 36108506 OWN - NLM STAT- MEDLINE DCOM- 20221219 LR - 20221220 IS - 1095-9157 (Electronic) IS - 0896-8411 (Linking) VI - 133 DP - 2022 Dec TI - zVAD alleviates experimental autoimmune hepatitis in mice by increasing the sensitivity of macrophage to TNFR1-dependent necroptosis. PG - 102904 LID - S0896-8411(22)00112-3 [pii] LID - 10.1016/j.jaut.2022.102904 [doi] AB - 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 membrane-permeable 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 pro-inflammatory 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-10-specific 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. CI - Copyright (c) 2022 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Li, Xuehui AU - Li X AD - State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. FAU - Zhang, Yongting AU - Zhang Y AD - State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. FAU - Wang, Jinping AU - Wang J AD - School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China. FAU - Li, Yuyu AU - Li Y AD - State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. FAU - Wang, Yuchong AU - Wang Y AD - State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. FAU - Shi, Fan AU - Shi F AD - State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. FAU - Hong, Liang AU - Hong L AD - State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. FAU - Li, Lanjuan AU - Li L AD - State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China. Electronic address: ljli@zju.edu.cn. FAU - Diao, Hongyan AU - Diao H AD - State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: diaohy@zju.edu.cn. LA - eng PT - Journal Article DEP - 20220913 PL - England TA - J Autoimmun JT - Journal of autoimmunity JID - 8812164 RN - 130068-27-8 (Interleukin-10) RN - 0 (benzyloxycarbonyl-valyl-alanyl-aspartic acid) RN - 0 (Oligopeptides) RN - 0 (Tnfrsf1a protein, mouse) SB - IM MH - Animals MH - Mice MH - *Chemical and Drug Induced Liver Injury, Chronic MH - Disease Models, Animal MH - *Hepatitis, Autoimmune/therapy MH - Interleukin-10 MH - *Macrophages MH - *Oligopeptides/therapeutic use MH - *Necroptosis OTO - NOTNLM OT - Liver injury OT - Macrophages OT - Necroptosis OT - TNFR1 OT - zVAD COIS- Declaration of competing interest The authors have no actual or potential conflicts of interest to declare. EDAT- 2022/09/16 06:00 MHDA- 2022/12/15 06:00 CRDT- 2022/09/15 18:24 PHST- 2022/06/26 00:00 [received] PHST- 2022/08/23 00:00 [revised] PHST- 2022/08/26 00:00 [accepted] PHST- 2022/09/16 06:00 [pubmed] PHST- 2022/12/15 06:00 [medline] PHST- 2022/09/15 18:24 [entrez] AID - S0896-8411(22)00112-3 [pii] AID - 10.1016/j.jaut.2022.102904 [doi] PST - ppublish SO - J Autoimmun. 2022 Dec;133:102904. doi: 10.1016/j.jaut.2022.102904. Epub 2022 Sep 13.