1. Academic Validation
  2. 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

  • Cell Mol Gastroenterol Hepatol. 2022 Aug 4;14(5):1103-1122. doi: 10.1016/j.jcmgh.2022.07.013.
Xin Liu 1 Wu Luo 2 Jiahao Chen 1 Chenghong Hu 1 Rumbidzai N Mutsinze 1 Xu Wang 1 Yanmei Zhang 3 Lijiang Huang 4 Wei Zuo 4 Guang Liang 5 Yi Wang 6
Affiliations

Affiliations

  • 1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 2 Medical Research Center, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 3 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 4 Xiangshan First People's Hospital Medical and Health Group, Affiliated Xiangshan Hospital of Wenzhou Medial University, Xiangshan, Zhejiang, China.
  • 5 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 6 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; Xiangshan First People's Hospital Medical and Health Group, Affiliated Xiangshan Hospital of Wenzhou Medial University, Xiangshan, Zhejiang, China. Electronic address: yi.wang1122@wmu.edu.cn.
Abstract

Background & aims: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Bone Marrow–Derived Macrophages; Deubiquitinating Enzymes; Severe Acute Pancreatitis; Systemic Inflammatory Response Syndrome.

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