Lin Gao1, Xiaowu Dong2, Weijuan Gong3,4, Wei Huang5, Jing Xue6, Qingtian Zhu3, Nan Ma1, Weiwei Chen1, Xianghui Fu7, Xiang Gao8, Zhaoyu Lin8, Yanbing Ding3, Juanjuan Shi6, Zhihui Tong1, Tingting Liu5, Rajarshi Mukherjee9, Robert Sutton9, Guotao Lu3, Weiqin Li1,2. 1. Center of Severe Acute Pancreatitis (CASP), Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, China. 2. Center of Severe Acute Pancreatitis (CASP), Department of Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, China. 3. Pancreatic Center, Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China. 4. Jiangsu Co-innovation Centre for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, China. 5. Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China. 6. State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Centre, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. 7. Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Centre of Biotherapy, Chengdu, China. 8. State Key Laboratory of Pharmaceutical Biotechnology, Department of Hepatopancreatobiliary Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Centre, Nanjing University, Nanjing, China. 9. Liverpool Pancreatitis Research Group, Liverpool University Hospitals NHS Foundation Trust and Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
Abstract
BACKGROUND AND PURPOSE: Pyroptosis is a lytic form of pro-inflammatory cell death characterised as caspase 1 dependent with canonical NLRP3 inflammasome-induced gasdermin D (GSDMD) activation. We aimed to investigate the role of acinar pyroptotic cell death in pancreatic injury and systemic inflammation in AP. EXPERIMENTAL APPROACH: Pancreatic acinar pyroptotic cell death pathway activation upon pancreatic toxin stimulation in vitro and in vivo was investigated. Effects of pharmacological (NLRP3 and caspase-1 inhibitors), constitutive (Nlrp3-/- , Casp1-/- and Gsdmd-/- ) and acinar cell conditional (Pdx1Cre Nlrp3Δ/Δ and Pdx1Cre GsdmdΔ/Δ ) genetic inhibition on pyroptotic acinar cell death, pancreatic necrosis and systemic inflammation were assessed using mouse AP models (caerulein, sodium taurocholate and l-arginine). Effects of Pdx1Cre GsdmdΔ/Δ versus myeloid conditional knockout (Lyz2Cre GsdmdΔ/Δ ) and Gsdmd-/- versus receptor-interacting protein 3 (RIP3) inhibitor were compared in CER-AP. KEY RESULTS: There was consistent pyroptotic acinar cell death upon pancreatic toxin stimulation both in vitro and in vivo, which was significantly reduced by pharmacological or genetic pyroptosis inhibition. Pdx1Cre GsdmdΔ/Δ but not Lyz2Cre GsdmdΔ/Δ mice showed significantly reduced pyroptotic acinar cell death, pancreatic necrosis and systemic inflammation in caerulein-AP. Co-application of RIP3 inhibitor on Gsdmd-/- mice further increased protection on caerulein-AP. CONCLUSION AND IMPLICATIONS: This work demonstrates a critical role for NLRP3 inflammasome and GSDMD activation-mediated pyroptosis in acinar cells, linking pancreatic necrosis and systemic inflammation in AP. Targeting pyroptosis signalling pathways holds promise for specific AP therapy.
BACKGROUND AND PURPOSE: Pyroptosis is a lytic form of pro-inflammatory cell death characterised as caspase 1 dependent with canonical NLRP3 inflammasome-induced gasdermin D (GSDMD) activation. We aimed to investigate the role of acinar pyroptotic cell death in pancreatic injury and systemic inflammation in AP. EXPERIMENTAL APPROACH: Pancreatic acinar pyroptotic cell death pathway activation upon pancreatic toxin stimulation in vitro and in vivo was investigated. Effects of pharmacological (NLRP3 and caspase-1 inhibitors), constitutive (Nlrp3-/- , Casp1-/- and Gsdmd-/- ) and acinar cell conditional (Pdx1Cre Nlrp3Δ/Δ and Pdx1Cre GsdmdΔ/Δ ) genetic inhibition on pyroptotic acinar cell death, pancreatic necrosis and systemic inflammation were assessed using mouse AP models (caerulein, sodium taurocholate and l-arginine). Effects of Pdx1Cre GsdmdΔ/Δ versus myeloid conditional knockout (Lyz2Cre GsdmdΔ/Δ ) and Gsdmd-/- versus receptor-interacting protein 3 (RIP3) inhibitor were compared in CER-AP. KEY RESULTS: There was consistent pyroptotic acinar cell death upon pancreatic toxin stimulation both in vitro and in vivo, which was significantly reduced by pharmacological or genetic pyroptosis inhibition. Pdx1Cre GsdmdΔ/Δ but not Lyz2Cre GsdmdΔ/Δ mice showed significantly reduced pyroptotic acinar cell death, pancreatic necrosis and systemic inflammation in caerulein-AP. Co-application of RIP3 inhibitor on Gsdmd-/- mice further increased protection on caerulein-AP. CONCLUSION AND IMPLICATIONS: This work demonstrates a critical role for NLRP3 inflammasome and GSDMD activation-mediated pyroptosis in acinar cells, linking pancreatic necrosis and systemic inflammation in AP. Targeting pyroptosis signalling pathways holds promise for specific AP therapy.
Authors: Abdullah Al Mamun; Suzia Aktar Suchi; Md Abdul Aziz; Muhammad Zaeem; Fahad Munir; Yanqing Wu; Jian Xiao Journal: Apoptosis Date: 2022-06-10 Impact factor: 5.561
Authors: Dongling Liu; Linlin Wen; Zhandong Wang; Yang Hai; Dan Yang; Yanying Zhang; Min Bai; Bing Song; Yongfeng Wang Journal: Front Med (Lausanne) Date: 2022-07-07