Serum amyloid A3 is required for caerulein-induced acute pancreatitis through induction of RIP3-dependent necroptosis
Serum amyloid A3 is required for caerulein-induced acute pancreatitis through induction of RIP3-dependent necroptosis
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血清淀粉样蛋白 A3 是雨蛙素通过诱导 RIP3 依赖性坏死性凋亡而诱发的急性胰腺炎所必需的
DOI：
10.1111/imcb.12382
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发表时间：
2020
影响因子：
4
通讯作者：
Sun Lei
中科院分区：
文献类型：
--
作者：
Yang Xinyi;Li Runsheng;Xu Lu;Qian Feng;Sun Lei
血清淀粉样蛋白A （SAA）是炎症性疾病的早期敏感生物标志物，但其在急性胰腺炎（AP）中的作用尚不清楚。在这里，我们使用小蛋白诱导的小鼠模型来研究SAA在AP和其他相关炎症反应中的作用。在我们的研究中，我们发现特定SAA亚型SAA3的表达在细小蛋白诱导的AP动物模型中显著升高。此外，与野生型小鼠相比，SAA3基因敲除（SAA3−/−）小鼠在给药后表现出更低的血清淀粉酶和脂肪酶水平，胰腺组织损伤和促炎细胞因子的产生。在saa3−/−小鼠中，AP相关的急性肺损伤也显著减弱。在体外实验中，胆囊收缩素和重组SAA3治疗显著诱导坏死下垂和细胞因子的产生。此外，我们发现SAA3对腺泡细胞坏死的调节作用是通过受体相互作用蛋白3 （RIP3）依赖的方式进行的。总的来说，我们的研究结果表明，SAA3通过诱导腺泡细胞中RIP3依赖性的坏死坏死途径是AP所必需的，并且是AP的潜在药物靶点。
Serum amyloid A (SAA) is an early and sensitive biomarker of inflammatory diseases, but its role in acute pancreatitis (AP) is still unclear. Here, we used a caerulein‐induced mouse model to investigate the role of SAA in AP and other related inflammatory responses. In our study, we found that the expression of a specific SAA isoform, SAA3, was significantly elevated in a caerulein‐induced AP animal model. In addition, SAA3‐knockout (Saa3−/−) mice showed lower serum levels of amylase and lipase, tissue damage and proinflammatory cytokine production in the pancreas compared with those of wild‐type mice in response to caerulein administration. AP‐associated acute lung injury was also significantly attenuated inSaa3−/−mice. In ourin vitroexperiments, treatment with cholecystokinin and recombinant SAA3 significantly induced necroptosis and cytokine production. Moreover, we found that the regulatory effect of SAA3 on acinar cell necroptosis was through a receptor‐interacting protein 3 (RIP3)‐dependent manner. Collectively, our findings indicate that SAA3 is required for AP by inducing an RIP3‐dependent necroptosis pathway in acinar cells and is a potential drug target for AP.