PINK1/PARK2 dependent mitophagy effectively suppresses NLRP3 inflammasome to alleviate acute pancreatitis
PINK1/PARK2 dependent mitophagy effectively suppresses NLRP3 inflammasome to alleviate acute pancreatitis
复制标题
PINK1/PARK2依赖性线粒体自噬有效抑制NLRP3炎性体缓解急性胰腺炎
DOI：
10.1016/j.freeradbiomed.2021.02.019
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发表时间：
2021
影响因子：
7.4
通讯作者：
Shi Keqing
中科院分区：
文献类型：
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作者：
Zhang Jie;Huang Weiguo;He Qikuan;Deng Tuo;Wu Boda;Huang Feifei;Bi Jiayang;Jin Yuepeng;Sun Hongwei;Zhang Qiyu;Shi Keqing
背景急性胰腺炎（acute pancreatitis， AP）是临床常见的消化系统急性炎症性疾病，可导致系统性炎症反应综合征（systemic inflammatory response syndrome， SIRS）和严重急性胰腺炎（severe acute pancreatitis， SAP）。据报道，PINK1/PARK2依赖性线粒体自噬在多种炎性疾病中发挥重要作用。然而，其在AP中的作用尚未阐明。方法首先以野生小鼠、PINK1-/小鼠和PARK2-/小鼠为实验对象，建立蛋白诱导的AP组和精氨酸诱导的SAP组。收集胰腺样本用于进一步研究线粒体动力学、线粒体自噬改变、NLRP3炎症途径等。此外，收集SAP患者外周血单个核细胞，检测有丝分裂相关指标的表达。结果证实AP和SAP模型均存在线粒体损伤。野生AP组PINK1、PARK2和线粒体自噬体的表达随时间升高，SAP组随时间降低。同样，SAP患者外周血单个核细胞中PINK1和PAKR2的表达也明显降低。此外，在PINK1-/和PARK2-/小鼠AP组中，炎症浸润更明显，凋亡和坏死水平升高，NLRP3炎症小体通路上调。注射MCC950后，PINK1-/和PARK2-/小鼠的NLRP3炎性小体产生明显减少，有效减轻了胰腺损伤和炎症细胞浸润。结论我们的研究表明，线粒体功能障碍激活了AP中PINK1/PARK2介导的线粒体自噬，而SAP中线粒体自噬受损，PINK1-/和PARK2-/-小鼠对SAP的发病更敏感，线粒体自噬缺失可导致NLRP3炎性体的形成。
BackgroundAcute pancreatitis (AP) is a clinically common acute inflammatory disease in digestive system, leading to systemic inflammatory response syndrome (SIRS) and severe acute pancreatitis (SAP). It was reported that PINK1/PARK2 dependent mitophagy played an important role in various inflammatory diseases. However, its role in AP has not been elucidated. Herein, we explore the effect of mitophagy in the pathogenesis of AP.MethodsFirstly, we established cerulein-induced AP group and arginine-induced SAP group based on wild, PINK1-/-and PARK2-/-mice. Pancreatic samples were harvested for further investing the mitochondrial dynamics, mitophagy alterations, NLRP3 inflammatory pathway etc. Furthermore, peripheral blood mononuclear cells from SAP patients were collected to examine the expression of mitophagy-related indicators. Additionally, the interrelationship between mitophagy and NLRP3 inflammasome was also explored in AP.ResultsIt was confirmed that mitochondria were damaged in both AP and SAP models. The expressions of PINK1, PARK2 and mitochondrial autophagosomes were elevated in wild AP group, which were decreased in SAP group over time. Similarly, the expressions of PINK1 and PAKR2 in peripheral blood mononuclear cells were significantly lower in SAP patients. Besides, in PINK1-/-and PARK2-/-mice AP groups, more pronounced inflammatory infiltration, increased apoptotic and necrotic levels and upregulated NLRP3 inflammasome pathway were detected. After injection with MCC950, NLRP3 inflammasome production was notably reduced in PINK1-/-and PARK2-/-mice, which effectively alleviated the pancreatic damage and inflammatory cell infiltration.ConclusionOur study suggested that mitochondrial dysfunction activated PINK1/PARK2-mediated mitophagy in AP, while mitophagy was impaired in SAP. PINK1-/-and PARK2-/-mice were more sensitive to onset of SAP and the deficiency of mitophagy could lead to the formation of NLRP3 inflammasome.