PMID- 32666684 OWN - NLM STAT- MEDLINE DCOM- 20210824 LR - 20210824 IS - 1474-9726 (Electronic) IS - 1474-9718 (Print) IS - 1474-9718 (Linking) VI - 19 IP - 8 DP - 2020 Aug TI - Aging aggravated liver ischemia and reperfusion injury by promoting STING-mediated NLRP3 activation in macrophages. PG - e13186 LID - 10.1111/acel.13186 [doi] LID - e13186 AB - Although aggravated liver injury has been reported in aged livers post-ischemia and reperfusion (IR), the underlying mechanism of innate immune activation of aged macrophages is not well understood. Here, we investigated whether and how Stimulator of interferon genes (STING) signaling regulated macrophage proinflammatory activation and liver IR injury. Mice were subjected to hepatic IR in vivo. Macrophages isolated from IR-stressed livers and bone marrow-derived macrophages (BMDMs) from young and aged mice were used for in vitro studies. Enhanced nucleotide-binding domain and leucine-rich repeat containing protein 3 (NLRP3) activation was found in both livers and macrophages of aged mice post-IR. NLRP3 knockdown in macrophages inhibited intrahepatic inflammation and liver injury in both young and aged mice. Interestingly, enhanced activation of the STING/ TANK-binding kinase 1 (TBK1) signaling pathway was observed in aged macrophages post-IR and mitochondria DNA (mtDNA) stimulation. STING suppression blocked over-activation of NLRP3 signaling and excessive secretion of proinflammatory cytokines/chemokines in the mtDNA-stimulated BMDMs from aged mice. More importantly, STING knockdown in macrophages abrogated the detrimental role of aging in aggravating liver IR injury and intrahepatic inflammation. Finally, peripheral blood from the recipients undergoing liver transplantation was collected and analyzed. The results showed that the elderly recipients had much higher levels of TNF-alpha, IL-6, IL-1beta, and IL-18 post-transplantation, indicating increased NLRP3 activation in lR-stressed livers of elderly recipients. In summary, our study demonstrated that the STING-NLRP3 axis was critical for the proinflammatory response of aged macrophages and would be a novel therapeutic target to reduce IR injury in elderly patients. CI - (c) 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. FAU - Zhong, Weizhe AU - Zhong W AD - Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. AD - 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. FAU - Rao, Zhuqing AU - Rao Z AD - Department of Anesthesiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. FAU - Rao, Jianhua AU - Rao J AD - Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. AD - 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. FAU - Han, Guoyong AU - Han G AD - Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. AD - 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. FAU - Wang, Ping AU - Wang P AD - Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. AD - 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. FAU - Jiang, Tao AU - Jiang T AD - Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. AD - 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. FAU - Pan, Xiongxiong AU - Pan X AD - Department of Anesthesiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. FAU - Zhou, Shun AU - Zhou S AD - Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. AD - 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. FAU - Zhou, Haoming AU - Zhou H AD - Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. AD - 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. FAU - Wang, Xuehao AU - Wang X AUID- ORCID: 0000-0001-5849-0098 AD - Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200714 PL - England TA - Aging Cell JT - Aging cell JID - 101130839 RN - 0 (Membrane Proteins) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Nlrp3 protein, mouse) RN - 0 (Sting1 protein, mouse) SB - IM MH - Age Factors MH - Animals MH - Liver/*blood supply MH - Macrophages/*metabolism/pathology MH - Male MH - Membrane Proteins/*metabolism MH - Mice MH - Mice, Inbred C57BL MH - NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism MH - Reperfusion Injury/*metabolism/pathology PMC - PMC7431827 OTO - NOTNLM OT - aging OT - and reperfusion injury OT - leucine-rich repeat containing protein 3 OT - liver ischemia OT - macrophage immune response OT - nucleotide-binding domain OT - stimulator of interferon genes COIS- The authors disclosed no conflicts of interest. EDAT- 2020/07/16 06:00 MHDA- 2021/08/25 06:00 PMCR- 2020/08/01 CRDT- 2020/07/16 06:00 PHST- 2019/12/10 00:00 [received] PHST- 2020/04/29 00:00 [revised] PHST- 2020/06/06 00:00 [accepted] PHST- 2020/07/16 06:00 [pubmed] PHST- 2021/08/25 06:00 [medline] PHST- 2020/07/16 06:00 [entrez] PHST- 2020/08/01 00:00 [pmc-release] AID - ACEL13186 [pii] AID - 10.1111/acel.13186 [doi] PST - ppublish SO - Aging Cell. 2020 Aug;19(8):e13186. doi: 10.1111/acel.13186. Epub 2020 Jul 14.