| First Author | Gao L | Year | 2021 |
| Journal | Br J Pharmacol | Volume | 178 |
| Issue | 17 | Pages | 3533-3552 |
| PubMed ID | 33871879 | Mgi Jnum | J:360249 |
| Mgi Id | MGI:7797578 | Doi | 10.1111/bph.15499 |
| Citation | Gao L, et al. (2021) Acinar cell NLRP3 inflammasome and gasdermin D (GSDMD) activation mediates pyroptosis and systemic inflammation in acute pancreatitis. Br J Pharmacol 178(17):3533-3552 |
| abstractText | 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. |
