Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 178, Issue 17, Pages 3533-3552Publisher
WILEY
DOI: 10.1111/bph.15499
Keywords
acinar cell death; acute pancreatitis; gasdermin D; NLRP3 inflammasome; pyroptosis
Categories
Funding
- Jiangsu Provincial Key Research and Development Program [BE2015685, BE2016749]
- National Natural Science Foundation of China [81570584, 81670588, 81800575, 81801970, 81973632]
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This study reveals the critical role of NLRP3 inflammasome and GSDMD activation-mediated pyroptosis in acinar cells, linking pancreatic necrosis and systemic inflammation in acute pancreatitis. Targeting pyroptosis signaling pathways holds promise for specific therapy for acute pancreatitis.
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(Delta/Delta) and Pdx1(Cre)Gsdmd(Delta/Delta)) 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(Delta/Delta) versus myeloid conditional knockout (Lyz2(Cre)Gsdmd(Delta/Delta)) 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(Delta/Delta) but not Lyz2(Cre)Gsdmd(Delta/Delta) 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.
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