2. Academic Validation
  3. Tryptanthrin suppresses multiple inflammasome activation to regulate NASH progression by targeting ASC protein

Tryptanthrin suppresses multiple inflammasome activation to regulate NASH progression by targeting ASC protein

  • Phytomedicine. 2024 Aug:131:155758. doi: 10.1016/j.phymed.2024.155758.
Lutong Ren 1,  Huijie Yang 2,  Hongbo Wang 3,  Shuanglin Qin 4,  Xiaoyan Zhan 5,  Hui Li 2,  Ziying Wei 2,  Zhie Fang 5,  Qiang Li 5,  Tingting Liu 6,  Wei Shi 5,  Jia Zhao 5,  Zhiyong Li 7,  Zhaofang Bai 8,  Guang Xu 9,  Jun Zhao 10
Affiliations

Affiliations

  • 1 Department of Pharmacy, Inner Mongolia People's Hospital, Hohhot, China; Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; China Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
  • 2 Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; China Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China.
  • 3 Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
  • 4 Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; China Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, China.
  • 5 Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; China Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
  • 6 Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; China Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, China.
  • 7 Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; China Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing, China.
  • 8 Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; China Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing, China. Electronic address: baizf2008@hotmail.com.
  • 9 China Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; School of Chinese Medicine, Capital Medical University, Beijing, China. Electronic address: guang_xu@ccmu.edu.cn.
  • 10 Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China. Electronic address: zhj68@263.net.
PMID: 38843643 DOI: 10.1016/j.phymed.2024.155758
Abstract

Background: The adaptor protein apoptosis-associated speck-like protein (ASC) containing a Caspase recruitment domain (CARD) can be activated through pyrin domain (PYD) interactions between sensors and ASC, and through CARD interactions between Caspase-1 and ASC. Although the majority of ternary inflammasome complexes depend on ASC, drugs targeting ASC protein remain scarce. After screening natural compounds from Isatidis Radixin, we found that tryptanthrin (TPR) could inhibit NLRP3-induced IL-1β and Caspase-1 production, but the underlying anti-inflammatory mechanisms remain to be elucidated.

Purpose: The purpose of this study was to determine the impact of TPR on the NLRP3, NLRC4, and AIM2 inflammasomes and the underlying mechanisms. Additionally, the efficacy of TPR was analysed in the further course of methionine- and choline-deficient (MCD)-induced NASH and lipopolysaccharide (LPS)-induced sepsis models of mice.

Methods: In vitro studies used bone marrow-derived macrophages to assess the anti-inflammatory activity of TPR, and the techniques included western blot, testing of intracellular K+ and CA2+, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), co-immunoprecipitation, ASC oligomerization assay, surface plasmon resonance (SPR), and molecular docking. We used LPS-induced sepsis models and MCD-induced NASH models in vivo to evaluate the effectiveness of TPR in inhibiting inflammatory diseases.

Results: Our observations suggested that TPR could inhibit NLRP3, NLRC4, and AIM2 inflammasome activation. As shown in a mouse model of inflammatory diseases caused by MCD-induced NASH and LPS-induced sepsis, TPR significantly alleviated the progression of diseases. TPR interrupted the interactions between ASC and NLRP3/NLRC4/AIM2 in the co-immunoprecipitation experiment, and stable binding of TPR to ASC was also evident in SPR experiments. The underlying mechanisms of anti-inflammatory activities of TPR might be associated with targeting ASC, in particular, PYD domain of ASC.

Conclusion: In general, the requirement for ASC in multiple inflammasome complexes makes TPR, as a novel broad-spectrum inflammasome inhibitor, potentially useful for treating a wide range of multifactorial inflammasome-related diseases.

Keywords

Adaptor protein ASC; Inflammasome; NASH; Sepsis; Tryptanthrin.

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