USP25 Deficiency Exacerbates Acute Pancreatitis via Up-Regulating TBK1-NF-κB Signaling in Macrophages.
USP25 Deficiency Exacerbates Acute Pancreatitis via Up-Regulating TBK1-NF-κB Signaling in Macrophages.
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USP 25缺乏通过上调巨噬细胞中TBK 1-NF-κB信号而加重急性胰腺炎
DOI：
10.1016/j.jcmgh.2022.07.013
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发表时间：
2022
影响因子：
7.2
通讯作者：
Wang, Yi
中科院分区：
文献类型：
--
作者：
Liu, Xin;Luo, Wu;Chen, Jiahao;Hu, Chenghong;Mutsinze, Rumbidzai N;Wang, Xu;Zhang, Yanmei;Huang, Lijiang;Zuo, Wei;Liang, Guang;Wang, Yi
重症急性胰腺炎很容易导致全身炎症反应综合征而死亡。已知巨噬细胞参与急性胰腺炎（AP）的病理生理学，并且巨噬细胞激活与疾病严重程度相关。在这项研究中，我们研究了泛素特异性蛋白酶 25（一种去泛素化酶和已知的巨噬细胞调节因子）在 AP 发病机制中的作用。我们在 Usp25-/- 小鼠和野生型小鼠中使用 L-精氨酸、雨蛙蛋白和缺乏胆碱的补充乙硫氨酸的饮食诱导的 AP 模型。我们还生成了骨髓 Usp25-/- 嵌合小鼠并启动了 L-精氨酸介导的 AP。从野生型和 Usp25-/- 小鼠中分离出原代腺泡细胞和骨髓来源的巨噬细胞，以剖析分子机制。我们的结果表明，在L-精氨酸、雨蛙蛋白和缺乏胆碱的补充乙硫氨酸的饮食诱导的AP模型中，Usp25缺乏会加剧胰腺和肺损伤、中性粒细胞和巨噬细胞浸润以及全身炎症反应。用 L-精氨酸攻击的骨髓 Usp25-/- 嵌合小鼠表明，巨噬细胞中的 Usp25 缺陷通过上调 TANK 结合激酶 1 (TBK1)-核因子-κB (NF-κB) 信号通路来加剧 AP。同样，体外数据证实，Usp25 缺陷会增强 TBK1–NF-κB 通路，导致骨髓来源的巨噬细胞中炎症细胞因子的表达增加。巨噬细胞中的 Usp25 缺陷会增强 TBK1–NF-κB 信号传导，炎症趋化因子和 I 型干扰素相关基因的诱导会加剧 AP 中的胰腺和肺损伤。
Severe acute pancreatitis can easily lead to systemic inflammatory response syndrome and death. Macrophages are known to be involved in the pathophysiology of acute pancreatitis (AP), and macrophage activation correlates with disease severity. In this study, we examined the role of ubiquitin-specific protease 25, a deubiquitinating enzyme and known regulator of macrophages, in the pathogenesis of AP. We used L-arginine, cerulein, and choline-deficient ethionine-supplemented diet–induced models of AP in Usp25-/- mice and wild-type mice. We also generated bone marrow Usp25-/- chimeric mice and initiated L-arginine–mediated AP. Primary acinar cells and bone marrow–derived macrophages were isolated from wild-type and Usp25-/- mice to dissect molecular mechanisms. Our results show that Usp25 deficiency exacerbates pancreatic and lung injury, neutrophil and macrophage infiltration, and systemic inflammatory responses in L-arginine, cerulein, and choline-deficient ethionine-supplemented diet–induced models of AP. Bone marrow Usp25-/- chimeric mice challenged with L-arginine show that Usp25 deficiency in macrophages exaggerates AP by up-regulating the TANK-binding kinase 1 (TBK1)–nuclear factor-κB (NF-κB) signaling pathway. Similarly, in vitro data confirm that Usp25 deficiency enhances the TBK1–NF-κB pathway, leading to increased expression of inflammatory cytokines in bone marrow–derived macrophages. Usp25 deficiency in macrophages enhances TBK1–NF-κB signaling, and the induction of inflammatory chemokines and type I interferon-related genes exacerbates pancreatic and lung injury in AP.