Center of Severe Acute Pancreatitis (CASP), Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
Center of Severe Acute Pancreatitis (CASP), Department of Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, China.
Br J Pharmacol. 2021 Sep;178(17):3533-3552. doi: 10.1111/bph.15499. Epub 2021 May 21.
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.
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 Nlrp3 and Pdx1 Gsdmd ) 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 Gsdmd versus myeloid conditional knockout (Lyz2 Gsdmd ) and Gsdmd versus receptor-interacting protein 3 (RIP3) inhibitor were compared in CER-AP.
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 Gsdmd but not Lyz2 Gsdmd 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.
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.
细胞焦亡是一种依赖半胱天冬酶 1（caspase-1）的促炎细胞程序性死亡形式，其特征是经典的核苷酸结合寡聚结构域样受体 3（NLRP3）炎性体诱导的 Gasdermin D（GSDMD）的激活。本研究旨在探讨胰腺损伤和急性胰腺炎（AP）全身炎症中腺泡细胞焦亡的作用。
研究了体外和体内胰腺毒素刺激后胰腺腺泡细胞焦亡途径的激活。使用胰酶诱导的 AP 模型（蛙皮素、牛磺胆酸钠和精氨酸），通过药理学（NLRP3 和 caspase-1 抑制剂）、组成性（Nlrp3、Casp1 和 Gsdmd）和腺泡细胞条件性（Pdx1 Nlrp3 和 Pdx1 Gsdmd）基因抑制，评估了对细胞焦亡、胰腺坏死和全身炎症的影响。在 CER-AP 中比较了 Pdx1 Gsdmd 与髓系条件性敲除（Lyz2 Gsdmd）和 Gsdmd 与受体相互作用蛋白 3（RIP3）抑制剂的作用。
在体外和体内胰腺毒素刺激后均存在一致的腺泡细胞焦亡，而通过药理学或基因焦亡抑制显著减少了焦亡。与 Lyz2 Gsdmd 相比，Pdx1 Gsdmd 小鼠在蛙皮素诱导的 AP 中表现出明显减少的细胞焦亡、胰腺坏死和全身炎症。在 Gsdmd 小鼠上应用 RIP3 抑制剂进一步增加了对蛙皮素诱导的 AP 的保护作用。
本研究证明了 NLRP3 炎性体和 GSDMD 激活介导的细胞焦亡在胰腺腺泡细胞中的关键作用，将胰腺坏死和 AP 全身炎症联系起来。靶向细胞焦亡信号通路有望为 AP 的特定治疗提供新策略。
