Acinar cell NLRP3 inflammasome and gasdermin D (GSDMD) activation mediates pyroptosis and systemic inflammation in acute pancreatitis
Acinar cell NLRP3 inflammasome and gasdermin D (GSDMD) activation mediates pyroptosis and systemic inflammation in acute pancreatitis
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DOI：
10.1111/bph.15499
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发表时间：
2021-05-21
影响因子：
7.3
通讯作者：
Li, Weiqin
中科院分区：
文献类型：
--
作者：
Gao, Lin;Dong, Xiaowu;Li, Weiqin
背景和目的细胞焦亡是促炎性细胞死亡的一种裂解形式，其特征是 caspase 1 依赖于典型的 NLRP3 炎症小体诱导的gasdermin D (GSDMD) 激活。我们的目的是研究腺泡焦亡细胞死亡在AP胰腺损伤和全身炎症中的作用。实验方法在体外和体内研究了胰腺毒素刺激后胰腺腺泡焦亡细胞死亡途径的激活。药理学（NLRP3和caspase-1抑制剂）、组成型（Nlrp3（-/-）、Casp1（-/-）和Gsdmd（-/-））和腺泡细胞条件性（Pdx1（Cre）Nlrp3（Delta/Delta）和Pdx1（Cre）Gsdmd（Delta/Delta））遗传抑制对焦亡腺泡细胞死亡、胰腺坏死和全身炎症的影响使用小鼠 AP 模型（雨伞素、牛磺胆酸钠和 L-精氨酸）进行评估。在 CER-AP 中比较了 Pdx1(Cre)Gsdmd(Delta/Delta) 与骨髓条件敲除 (Lyz2(Cre)Gsdmd(Delta/Delta)) 和 Gsdmd(-/-) 与受体相互作用蛋白 3 (RIP3) 抑制剂的效果。 主要结果 在体外和体内，胰腺毒素刺激后，腺泡细胞均出现一致的焦亡性腺泡细胞死亡，通过药物或遗传可显着减少这种死亡。焦亡抑制。 Pdx1(Cre)Gsdmd(Delta/Delta) 但 Lyz2(Cre)Gsdmd(Delta/Delta) 小鼠在 caerulein-AP 中表现出焦亡性腺泡细胞死亡、胰腺坏死和全身炎症显着减少。在 Gsdmd(-/-) 小鼠上共同应用 RIP3 抑制剂进一步增强了对雨伞素-AP 的保护。 结论和意义这项工作证明了 NLRP3 炎性体和 GSDMD 激活介导的腺泡细胞焦亡的关键作用，将 AP 中的胰腺坏死和全身炎症联系起来。靶向细胞焦亡信号通路为特定的 AP 治疗带来了希望。
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.