2. Academic Validation
  3. Tricyclic antidepressants induce liver inflammation by targeting NLRP3 inflammasome activation

Tricyclic antidepressants induce liver inflammation by targeting NLRP3 inflammasome activation

  • Cell Commun Signal. 2023 May 25;21(1):123. doi: 10.1186/s12964-023-01128-x.
Wenqing Mu # 1 2 3,  Guang Xu # 4 5 6,  Zhilei Wang # 1 7,  Qiang Li 1 8,  Siqiao Sun 1 8,  Qin Qin 1 8,  Zhiyong Li 1 8,  Wei Shi 1 8,  Wenzhang Dai 1 8,  Xiaoyan Zhan 1 8,  Jiabo Wang 1 8,  Zhaofang Bai 9 10,  Xiaohe Xiao 11 12
Affiliations

Affiliations

  • 1 Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, 100039, China.
  • 2 State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, 215123, Jiangsu, China.
  • 3 School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China.
  • 4 Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, 100039, China. guang_xu@ccmu.edu.cn.
  • 5 School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China. guang_xu@ccmu.edu.cn.
  • 6 Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. guang_xu@ccmu.edu.cn.
  • 7 TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
  • 8 Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.
  • 9 Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, 100039, China. baizf2008@hotmail.com.
  • 10 Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. baizf2008@hotmail.com.
  • 11 Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, 100039, China. pharmacy_302@126.com.
  • 12 Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. pharmacy_302@126.com.
  • # Contributed equally.
PMID: 37231437 DOI: 10.1186/s12964-023-01128-x
Abstract

Background: Idiosyncratic drug-induced liver injury (IDILI) is common in hepatology practices and, in some cases, lethal. Increasing evidence show that tricyclic antidepressants (TCAs) can induce IDILI in clinical applications but the underlying mechanisms are still poorly understood.

Methods: We assessed the specificity of several TCAs for NLRP3 inflammasome via MCC950 (a selective NLRP3 Inhibitor) pretreatment and NLRP3 knockout (NLRP3-/-) BMDMs. Meanwhile, the role of NLRP3 inflammasome in the TCA nortriptyline-induced hepatotoxicity was demonstrated in NLRP3-/- mice.

Results: We reported here that nortriptyline, a common TCA, induced idiosyncratic hepatotoxicity in a NLRP3 inflammasome-dependent manner in mildly inflammatory states. In parallel in vitro studies, nortriptyline triggered the inflammasome activation, which was completely blocked by NLRP3 deficiency or MCC950 pretreatment. Furthermore, nortriptyline treatment led to mitochondrial damage and subsequent mitochondrial Reactive Oxygen Species (mtROS) production resulting in aberrant activation of the NLRP3 inflammasome; a selective mitochondrial ROS inhibitor pretreatment dramatically abrogated nortriptyline-triggered the NLRP3 inflammasome activation. Notably, exposure to other TCAs also induced aberrant activation of the NLRP3 inflammasome by triggering upstream signaling events.

Conclusion: Collectively, our findings revealed that the NLRP3 inflammasome may act as a crucial target for TCA agents and suggested that the core structures of TCAs may contribute to the aberrant activation of NLRP3 inflammasome induced by them, an important factor involved in the pathogenesis of TCA-induced liver injury. Video Abstract.

Keywords

Antidepressant; Idiosyncratic hepatotoxicity; NLRP3 inflammasome; Nortriptyline; Tricyclic antidepressant.

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