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Acinar cell NLRP3 inflammasome and gasdermin D (GSDMD) activation mediates pyroptosis and systemic inflammation in acute pancreatitis.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2021 Sep; Vol. 178 (17), pp. 3533-3552. Date of Electronic Publication: 2021 May 21. - Publication Year :
- 2021
-
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.<br />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 <superscript>-/-</superscript> , Casp1 <superscript>-/-</superscript> and Gsdmd <superscript>-/-</superscript> ) and acinar cell conditional (Pdx1 <superscript>Cre</superscript> Nlrp3 <superscript>Δ/Δ</superscript> and Pdx1 <superscript>Cre</superscript> Gsdmd <superscript>Δ/Δ</superscript> ) 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 <superscript>Cre</superscript> Gsdmd <superscript>Δ/Δ</superscript> versus myeloid conditional knockout (Lyz2 <superscript>Cre</superscript> Gsdmd <superscript>Δ/Δ</superscript> ) and Gsdmd <superscript>-/-</superscript> versus receptor-interacting protein 3 (RIP3) inhibitor were compared in CER-AP.<br />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 <superscript>Cre</superscript> Gsdmd <superscript>Δ/Δ</superscript> but not Lyz2 <superscript>Cre</superscript> Gsdmd <superscript>Δ/Δ</superscript> mice showed significantly reduced pyroptotic acinar cell death, pancreatic necrosis and systemic inflammation in caerulein-AP. Co-application of RIP3 inhibitor on Gsdmd <superscript>-/-</superscript> mice further increased protection on caerulein-AP.<br />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.<br /> (© 2021 The British Pharmacological Society.)
- Subjects :
- 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
Phosphate-Binding Proteins
Pancreatitis chemically induced
Pyroptosis
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5381
- Volume :
- 178
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 33871879
- Full Text :
- https://doi.org/10.1111/bph.15499