Reduction in O-GlcNAcylation Mitigates the Severity of Inflammatory Response in Cerulein-Induced Acute Pancreatitis in a Mouse Model.
Reduction in O-GlcNAcylation Mitigates the Severity of Inflammatory Response in Cerulein-Induced Acute Pancreatitis in a Mouse Model.
复制标题
DOI：
10.3390/biology11030347
复制
发表时间：
2022-02-22
期刊：
影响因子：
4.2
通讯作者：
Alejandro EU
中科院分区：
文献类型：
--
作者：
Moore M;Avula N;Wong A;Beetch M;Jo S;Alejandro EU
急性胰腺炎（acute pancreatitis，AP）是一种常见病，在过去的40年中，AP的发病率在全球范围内呈上升趋势。目前对促进一个人对这种炎症性疾病易感性的分子基础的理解还不太清楚。蛋白质O-GlcNAc转移酶（OGT）是一种在胰腺中高度表达的胞质/核/线粒体翻译后糖基化酶。在这里，我们提出OGT，这已经与调节许多炎症反应，如NFκB信号，提供了机制联系AP的诱导和易感性。在这项研究中，产生了胰腺OGT损失的小鼠模型，并进行雨蛙肽，一种常见的胰腺炎诱导剂。胰腺OGT缺陷小鼠表现出AP严重程度降低，与胰腺中炎症标志物减少以及巨噬细胞数量减少相关。总之，这些数据表明，OGT是一种分子驱动器，促进雨蛙素诱导的AP在体内。 急性胰腺炎（AP）涉及过早的胰蛋白酶原激活，其介导了导致胰腺损伤早期阶段的促炎信号级联。转录因子κB（NF-κB）的激活和促炎介质的分泌是AP的主要事件。O-GlcNAc转移酶（OGT）是一种应激敏感酶，近年来在体外研究中发现其参与AP中NF-κB的活化和炎症反应。本研究旨在确定在小鼠模型中胰腺特异性转基因OGT减少是否影响体内AP的严重程度。将8周龄时胰腺OGT降低（OGTPanc+/−）的小鼠随机分配至蛙皮素组（可诱导胰腺炎）或盐水注射组。AP通过淀粉酶水平升高和组织学分析证实。组织学评分表明OGTPanc+/−小鼠AP的严重程度降低。此外，与对照组相比，OGTPPanc +/−中的血清脂肪酶、LDH和TNF-α对雨蛙肽治疗的反应没有显著增加，表明该模型中AP诱导减弱。我们的研究揭示了降低胰腺OGT水平对胰腺炎严重程度的影响，为进一步研究OGT在AP病理中的作用奠定了基础。
Acute pancreatitis (AP) is a common disease with significant co-morbidity and increasing global incidence over the past 40 years. Current understanding of molecular underpinnings that facilitates one’s susceptibility to this inflammatory disease is less understood. The protein O-GlcNAc Transferase (OGT) is a cytosolic/nuclear/mitochondrial post-translational glycosylation enzyme that is highly expressed in the pancreas. Here, we propose that OGT, which has been associated with regulating many inflammatory responses such as NFκB signaling, provides the mechanistic link to AP induction and susceptibility. In this study, a mouse model with pancreatic OGT loss was generated and subjected to cerulein, a common pancreatitis inducer. Pancreas OGT-deficient mice exhibited reduced severity of AP, associated with reduced inflammatory markers as well as decreased macrophage population in the pancreas. In conclusion, these data indicate that OGT is a molecular driver that facilitates cerulein-induced AP in vivo. Acute pancreatitis (AP) involves premature trypsinogen activation, which mediates a cascade of pro-inflammatory signaling that causes early stages of pancreatic injury. Activation of the transcription factor κB (NF-κB) and secretion of pro-inflammatory mediators are major events in AP. O-GlcNAc transferase (OGT), a stress-sensitive enzyme, was recently implicated to regulate NF-κB activation and inflammation in AP in vitro. This study aims to determine whether a pancreas-specific transgenic reduction in OGT in a mouse model affects the severity of AP in vivo. Mice with reduced pancreatic OGT (OGTPanc+/−) at 8 weeks of age were randomized to cerulein, which induces pancreatitis, or saline injections. AP was confirmed by elevated amylase levels and on histological analysis. The histological scoring demonstrated that OGTPanc+/− mice had decreased severity of AP. Additionally, serum lipase, LDH, and TNF-α in OGTPanc+/− did not significantly increase in response to cerulein treatment as compared to controls, suggesting attenuated AP induction in this model. Our study reveals the effect of reducing pancreatic OGT levels on the severity of pancreatitis, warranting further investigation on the role of OGT in the pathology of AP.
登录
查看更多内容
影响因子：
8.8
作者：
Lockridge A;Jo S;Gustafson E;Damberg N;Mohan R;Olson M;Abrahante JE;Alejandro EU
通讯作者：
Alejandro EU
影响因子：
15.9
作者：
Halangk, W;Lerch, MM;Deussing, J
通讯作者：
Deussing, J
影响因子：
12.6
作者：
Gorelick, Fred S.;Thrower, Edwin
通讯作者：
Thrower, Edwin
影响因子：
5.6
作者：
Kim MJ;Kim HS;Lee S;Min KY;Choi WS;You JS
通讯作者：
You JS
影响因子：
8.8
作者：
Alejandro EU;Bozadjieva N;Kumusoglu D;Abdulhamid S;Levine H;Haataja L;Vadrevu S;Satin LS;Arvan P;Bernal-Mizrachi E
通讯作者：
Bernal-Mizrachi E