Serum amyloid A3 is required for caerulein-induced acute pancreatitis through induction of RIP3-dependent necroptosis.,Immunology and Cell Biology

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Serum amyloid A3 is required for caerulein-induced acute pancreatitis through induction of RIP3-dependent necroptosis.
Immunology and Cell Biology ( IF 3.2 ) Pub Date : 2020-07-28 , DOI: 10.1111/imcb.12382
Xinyi Yang ₁ , Runsheng Li ₂ , Lu Xu ₁ , Feng Qian _{1,

3} , Lei Sun ₁

Affiliation

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 in Saa3^−/− mice. In our in vitro experiments, 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.

中文翻译：

血清淀粉样蛋白 A3 是通过诱导 RIP3 依赖的坏死性凋亡引起的雨蛙肽诱导的急性胰腺炎所必需的。

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) 中的作用仍不清楚。在这里，我们使用雨蛙素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 的表达在雨蛙肽诱导的 AP 动物模型中显着升高。此外，与野生型小鼠相比，SAA3 基因敲除 ( Saa3 ^-/- ) 小鼠的血清淀粉酶和脂肪酶水平、组织损伤和促炎细胞因子的产生均低于野生型小鼠，以响应金盏花素给药。在Saa3 ^-/-小鼠中，AP 相关的急性肺损伤也显着减轻。在我们体外在实验中，用缩胆囊素和重组 SAA3 处理显着诱导了坏死性凋亡和细胞因子的产生。此外，我们发现 SAA3 对腺泡细胞坏死性凋亡的调节作用是通过受体相互作用蛋白 3 (RIP3) 依赖的方式实现的。总的来说，我们的研究结果表明，SAA3 通过在腺泡细胞中诱导 RIP3 依赖的坏死性凋亡途径是 AP 所必需的，并且是 AP 的潜在药物靶点。

更新日期：2020-07-28

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