PMID- 31625631 OWN - NLM STAT- MEDLINE DCOM- 20201005 LR - 20211204 IS - 1440-1711 (Electronic) IS - 0818-9641 (Print) IS - 0818-9641 (Linking) VI - 98 IP - 1 DP - 2020 Jan TI - Hyperglycemia aggravates acute liver injury by promoting liver-resident macrophage NLRP3 inflammasome activation via the inhibition of AMPK/mTOR-mediated autophagy induction. PG - 54-66 LID - 10.1111/imcb.12297 [doi] AB - Although the detrimental effects of diabetes mellitus/hyperglycemia have been observed in many liver disease models, the function and mechanism of hyperglycemia regulating liver-resident macrophages, Kupffer cells (KCs), in thioacetamide (TAA)-induced liver injury remain largely unknown. In this study, we evaluated the role of hyperglycemia in regulating NOD-like receptor family pyrin domain-containing 3 protein (NLRP3) inflammasome activation by inhibiting autophagy induction in KCs in the TAA-induced liver injury model. Type I diabetes/hyperglycemia was induced by streptozotocin treatment. Compared with the control group, hyperglycemic mice exhibited a significant increase in intrahepatic inflammation and liver injury. Enhanced NLRP3 inflammasome activation was detected in KCs from hyperglycemic mice, as shown by increased gene induction and protein levels of NLRP3, cleaved caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain and interleukin-1beta, compared with control mice. NLRP3 inhibition by its antagonist CY-09 effectively suppressed inflammasome activation in KCs and attenuated liver injury in hyperglycemic mice. Furthermore, inhibited autophagy activation was revealed by transmission electron microscope detection, decreased LC3B protein expression and p-62 protein degradation in KCs isolated from TAA-stressed hyperglycemic mice. Interestingly, inhibited 5' AMP-activated protein kinase (AMPK) but enhanced mammalian target of rapamycin (mTOR) activation was found in KCs from TAA-stressed hyperglycemic mice. AMPK activation by its agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or mTOR signaling knockdown by small interfering RNA restored autophagy activation, and subsequently, inhibited NLRP3 inflammasome activation in KCs, leading to ultimately reduced TAA-induced liver injury in the hyperglycemic mice. Our findings demonstrated that hyperglycemia aggravated TAA-induced acute liver injury by promoting liver-resident macrophage NLRP3 inflammasome activation via inhibiting AMPK/mTOR-mediated autophagy. This study provided a novel target for prevention of toxin-induced acute liver injury under hyperglycemia. CI - (c) 2019 The Authors. Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of Australasian Society for Immunology Inc. FAU - Wang, Qi AU - Wang Q AUID- ORCID: 0000-0002-0349-9260 AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China. AD - Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. AD - NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China. FAU - Wei, Song AU - Wei S AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China. AD - Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. AD - NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China. AD - School of Medical, Southeast University, Nanjing, China. FAU - Zhou, Shun AU - Zhou S AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China. AD - Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. AD - NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China. FAU - Qiu, Jiannan AU - Qiu J AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China. AD - Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. AD - NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China. FAU - Shi, Chenyu AU - Shi C AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China. AD - Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. AD - NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China. FAU - Liu, Rui AU - Liu R AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China. AD - Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. AD - NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China. FAU - Zhou, Haoming AU - Zhou H AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China. AD - Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. AD - NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China. FAU - Lu, Ling AU - Lu L AD - Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China. AD - Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. AD - NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China. AD - School of Medical, Southeast University, Nanjing, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191119 PL - United States TA - Immunol Cell Biol JT - Immunology and cell biology JID - 8706300 RN - 0 (Inflammasomes) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Nlrp3 protein, mouse) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM MH - AMP-Activated Protein Kinases/*immunology MH - Animals MH - Autophagic Cell Death/*immunology MH - Hyperglycemia/*immunology/pathology MH - Inflammasomes/*immunology MH - Liver Failure, Acute/*immunology/pathology MH - Macrophages/*immunology/pathology MH - Male MH - Mice MH - NLR Family, Pyrin Domain-Containing 3 Protein/*immunology MH - Signal Transduction/*immunology MH - TOR Serine-Threonine Kinases/*immunology PMC - PMC7004066 OTO - NOTNLM OT - AMPK OT - mTOR OT - Kupffer cell OT - NLRP3 inflammasome OT - autophagy OT - hyperglycemia OT - liver injury OT - thioacetamide COIS- All authors declare no conflict of interest. EDAT- 2019/10/19 06:00 MHDA- 2020/10/06 06:00 PMCR- 2020/02/06 CRDT- 2019/10/19 06:00 PHST- 2019/06/04 00:00 [received] PHST- 2019/09/08 00:00 [revised] PHST- 2019/10/15 00:00 [revised] PHST- 2019/10/15 00:00 [accepted] PHST- 2019/10/19 06:00 [pubmed] PHST- 2020/10/06 06:00 [medline] PHST- 2019/10/19 06:00 [entrez] PHST- 2020/02/06 00:00 [pmc-release] AID - IMCB12297 [pii] AID - 10.1111/imcb.12297 [doi] PST - ppublish SO - Immunol Cell Biol. 2020 Jan;98(1):54-66. doi: 10.1111/imcb.12297. Epub 2019 Nov 19.