Acinar cell NLRP3 inflammasome and gasdermin D (GSDMD) activation mediates pyroptosis and systemic inflammation in 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 ^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.
(© 2021 The British Pharmacological Society.)