MARCH9 通过介导 NOX2 泛素化来减轻急性胰腺炎中 NLRP3 炎性小体依赖性胰腺细胞焦亡。
MARCH9 Mediates NOX2 Ubiquitination to Alleviate NLRP3 Inflammasome-Dependent Pancreatic Cell Pyroptosis in Acute Pancreatitis.
机构信息
From the Department of Gastroenterology, The Affiliated Changzhou No.2 People's Hospital with Nanjing Medical University, Changzhou, China.
出版信息
Pancreas. 2023 Jan 1;52(1):e62-e69. doi: 10.1097/MPA.0000000000002225.
OBJECTIVE
The pathogenesis of acute pancreatitis mainly involves NLRP3 inflammasome-mediated pancreatic cell injury, although regulators of this inflammasome machinery are still not fully identified. Membrane-associated RING-CH 9 (MARCH9) is a member of MARCH-type finger proteins, which regulates innate immunity through catalyzing polyubiquitination of critical immune factors. The aim of present research is to examine the function of MARCH9 in acute pancreatitis.
METHODS
Cerulein-induced acute pancreatitis was established on pancreatic cell line AR42J and rat model. Reactive oxygen species (ROS) accumulation and NLRP3 inflammasome-dependent cell pyroptosis in pancreas were examined by flow cytometry.
RESULTS
MARCH9 was downregulated by cerulein, but overexpressing MARCH9 could inhibit NLRP3 inflammasome activation and ROS accumulation, thus suppressing pancreatic cell pyroptosis and mitigating pancreatic injury. We further uncovered that the mechanism underlying such an effect of MARCH9 is through mediating the ubiquitination of NADPH oxidase-2, whose deficiency reduces cellular ROS accumulation and inflammasome formation.
CONCLUSIONS
Our results suggested that MARCH9 suppresses NLRP3 inflammasome-mediated pancreatic cell injury through mediating the ubiquitination and degradation of NADPH oxidase-2, which compromises ROS generation and NLRP3 inflammasomal activation.
目的
急性胰腺炎的发病机制主要涉及 NLRP3 炎性体介导的胰腺细胞损伤，尽管该炎性体机制的调节剂尚未完全确定。膜相关环指蛋白 9（MARCH9）是 MARCH 型手指蛋白的成员，通过催化关键免疫因子的多泛素化来调节先天免疫。本研究旨在研究 MARCH9 在急性胰腺炎中的作用。
方法
在胰腺细胞系 AR42J 和大鼠模型上建立了胆酸钠诱导的急性胰腺炎。通过流式细胞术检测胰腺中活性氧（ROS）的积累和 NLRP3 炎性体依赖性细胞焦亡。
结果
胆酸钠下调了 MARCH9，但过表达 MARCH9 可以抑制 NLRP3 炎性体的激活和 ROS 的积累，从而抑制胰腺细胞焦亡和减轻胰腺损伤。我们进一步发现，MARCH9 发挥这种作用的机制是通过介导 NADPH 氧化酶-2 的泛素化，其缺失减少了细胞内 ROS 的积累和炎性体的形成。
结论
我们的结果表明，MARCH9 通过介导 NADPH 氧化酶-2 的泛素化和降解来抑制 NLRP3 炎性体介导的胰腺细胞损伤，从而影响 ROS 的产生和 NLRP3 炎性体的激活。
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