Dichotomy between Receptor-Interacting Protein 1-and Receptor-Interacting Protein 3-Mediated Necroptosis in Experimental Pancreatitis
Dichotomy between Receptor-Interacting Protein 1-and Receptor-Interacting Protein 3-Mediated Necroptosis in Experimental Pancreatitis
复制标题
实验性胰腺炎中受体相互作用蛋白 1 和受体相互作用蛋白 3 介导的坏死性凋亡之间的二分法
DOI：
10.1016/j.ajpath.2016.12.021
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发表时间：
2017-05-01
影响因子：
6
通讯作者：
Hu，Guoyong
中科院分区：
文献类型：
--
作者：
Wu，Jianghong;Mulatibieke，Tunike;Hu，Guoyong
胰腺腺泡细胞坏死和炎症反应是急性胰腺炎（AP）的两个重要病理过程，决定着AP的严重程度和转归。近年来的研究表明，坏死性凋亡（necroptosis）是一种程序性坏死，参与了AP的发病过程，但其机制尚不清楚。我们研究了坏死体组分的表达，包括受体相互作用蛋白（RIP）1、RIP 3和混合谱系激酶结构域样（MLKL），以及胰腺炎相关坏死性凋亡的分子机制。我们发现RIP 3和磷酸化MLKL的表达与坏死程度呈正相关，而RIP 1的表达与坏死程度呈负相关。药理学抑制RIP 1激酶活性对雨蛙肽/胆囊收缩素-8诱导的AP没有保护作用，但用siRNA敲低RIP 1可增加腺泡细胞坏死和抑制NF-κB活化。RIP 1抑制导致RIP 3表达增强。RIP 3和MLKL抑制可减少腺泡细胞坏死，其中RIP 3的抑制可降低MLKL的磷酸化水平。RIP 3抑制对胰蛋白酶原活化没有影响，但部分抑制炎性小体活化。我们的研究有力地表明，RIP 1和RIP 3之间的失衡使细胞死亡转变为坏死，这揭示了AP的新的分子发病机制，并可能为其他坏死相关疾病的新型治疗药物的开发提供见解。
Pancreatic acinar cell necrosis and inflammatory responses are two key pathologic processes in acute pancreatitis (AP), which determines the severity and outcome of the disease. Recent studies suggest that necroptosis, a programed form of necrosis, is involved in the pathogenesis of AP, but the underlying mechanisms remain unknown. We investigated the expression of necrosome components, including receptor-interacting protein (RIP) 1, RIP3, and mixed lineage kinase domain-like (MLKL), and the molecular mechanisms in pancreatitis-associated necroptosis. We found that RIP3 and phosphorylated MLKL expression was positively related to the degree of necrosis, whereas RIP1 expression was negatively related to the degree of necrosis. Pharmacologic inhibition of RIP1 kinase activity exerted no protection against caerulein/cholecystokinin-8–induced AP, but knockdown of RIP1 with siRNA increased acinar cell necrosis and inhibition of NF-κB activation. RIP1 inhibition led to enhanced RIP3 expression. RIP3 and MLKL inhibition decreased acinar cell necrosis, in which the inhibition of RIP3 reduced the phosphorylation level of MLKL. RIP3 inhibition had no effect on trypsinogen activation but partly inhibited inflammasome activation. Our study strongly suggests that the imbalance between RIP1 and RIP3 shifts the cell death to necrosis, which unravels a new molecular pathogenesis of mechanism of AP and may provide insight into the development of novel therapeutic agent for other necrosis-related diseases.