Acinar cell NLRP3 inflammasome and gasdermin D (GSDMD) activation mediates pyroptosis and systemic inflammation in acute pancreatitis. (21st May 2021)

• Record Type: Journal Article
• Authors: Gao, Lin; Dong, Xiaowu; Gong, Weijuan; Huang, Wei; Xue, Jing; Zhu, Qingtian; Ma, Nan; Chen, Weiwei; Fu, Xianghui; Gao, Xiang; Lin, Zhaoyu; Ding, Yanbing; Shi, Juanjuan; Tong, Zhihui; Liu, Tingting; Mukherjee, Rajarshi; Sutton, Robert; Lu, Guotao; Li, Weiqin
• Is Part Of: British journal of pharmacology. Volume 178:Number 17(2021)
• Page Start: 3533
• Page End: 3552
• Publication Date: 2021-05-21
• Subjects: acinar cell death -- acute pancreatitis -- gasdermin D -- NLRP3 inflammasome -- pyroptosis; Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.15499
• Languages: English
• ISSNs: 0007-1188

Abstract

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 ( Pdx1 Cre Nlrp3 Δ/Δ and Pdx1 Cre Gsdmd Δ/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 Pdx1 Cre Gsdmd Δ/Δ versus myeloid conditional knockout ( Lyz2 Cre Gsdmd Δ/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. Pdx1 Cre Gsdmd Δ/Δ but not Lyz2 Cre Gsdmd Δ/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.