Acinar cell NLRP3 inflammasome and gasdermin D (GSDMD) activation mediates pyroptosis and systemic inflammation in acute pancreatitis

Lin Gao; Xiaowu Dong; Weijuan Gong; Wei Huang; Jing Xue; Qingtian Zhu; Nan Ma; Weiwei Chen; Xianghui Fu; Xiang Gao; Zhaoyu Lin; Yanbing Ding; Juanjuan Shi; Zhihui Tong; Tingting Liu; Rajarshi Mukherjee; Robert Sutton; Guotao Lu; Weiqin Li

doi:10.1111/bph.15499

Acinar cell NLRP3 inflammasome and gasdermin D (GSDMD) activation mediates pyroptosis and systemic inflammation in acute pancreatitis

Br J Pharmacol. 2021 Sep;178(17):3533-3552. doi: 10.1111/bph.15499. Epub 2021 May 21.

Authors

Lin Gao¹, Xiaowu Dong², Weijuan Gong^{3

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 Li^{1

2}

Affiliations

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.

PMID: 33871879
DOI: 10.1111/bph.15499

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.

Keywords: NLRP3 inflammasome; acinar cell death; acute pancreatitis; gasdermin D; pyroptosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acinar Cells / metabolism
Acute Disease
Animals
Inflammasomes / metabolism
Inflammation
Intracellular Signaling Peptides and Proteins
Mice
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Pancreatitis* / chemically induced
Phosphate-Binding Proteins
Pyroptosis*

Substances

Gsdmd protein, mouse
Inflammasomes
Intracellular Signaling Peptides and Proteins
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Phosphate-Binding Proteins