Psoralidin, a major component of Psoraleae Fructus, induces inflammasome activation and idiosyncratic liver injury
Introduction
Idiosyncratic drug-induced liver injury (IDILI) is a relatively rare but important contributor to liver disease [1], [2], [3] that can occur after exposure to various drugs, herbs, and dietary supplements [2]. IDILI continues to be an important issue threatening human health as the drugs that cause this adverse reaction have not been identified via current preclinical testing. Furthermore, a lack of understanding of the mechanisms underlying this adverse reaction hinders the development of prevention measures [4]. Traditional Chinese medicine (TCM) is generally considered to be nontoxic and safe. Liver injury caused by TCMs, such as Polygonum multiflorum [5], Psoraleae fructus (PF) and Epimedii folium [6], has been frequently reported in recent years. However, the mechanism underlying the hepatotoxicity of these drugs is yet to be fully explored. It is urgently necessary to develop and validate a test for identifying the drugs that cause IDILI and to understand their precise mechanisms of action.
Increasing evidence indicates that the majority of IDILI cases are immune-mediated [7], [8]. The aberrant activation of inflammasomes could be an important factor that induces the immune responses that lead to liver diseases, including IDILI, liver fibrosis, and nonalcoholic/alcoholic steatohepatitis [9], [10], [11]. Inflammasomes are protein complexes that typically comprise a sensor, such as NOD-like receptor family pyrin domain-containing 3 (NLRP3) or NLRC4, an apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) and the zymogen pro-caspase-1 [12]. Inflammasome assembly occurs in response to the presence of diverse pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) which are sensed by the body [13]. The inflammasome platform leads to the activation of caspase-1 through self-cleavage, which further induces pyroptosis and the maturation of interleukin 1β (IL-1β) through proteolytic cleavage of pro-IL-1β [14].
PF is the fruit of Psoralea corylifolia L., which is widely used in Asia, primarily for the treatment of osteoporosis and vitiligo [15]. Recent studies have demonstrated that PF has diverse biological properties, including anticancer, osteogenic, anti-inflammatory, antibacterial, and estrogenic activities [16], [17]. Therefore, PF has a wide variety of clinical applications. However, it has been found through clinical trial reports that PF can cause a number of adverse reactions, of which the most prominent is hepatotoxicity [18]. In our previous study, we found that PF can induce an increase in aminotransferase activity, include liver injury, and increased the production of IL-1β [6]. As the production of IL-1β results from inflammasome activation, we inferred that PF may cause liver injury by inducing inflammasome activation. In this study, we evaluated the effect of eight active compounds in PF on inflammasome activation and found that psoralidin, the major active and metabolic constituent of PF, could induce the activation of inflammasome and lead to an uncontrolled immune response and the idiosyncratic liver injury in vivo.
Section snippets
Animals and treatment
For the in vivo studies, 6–8-week-old C57BL/6 female mice were purchased from SPF Biotechnology Co. Ltd. (License No. SCXK2019-0010, Beijing, China). NLRP3-knockout (NLRP3-/-) mice were kindly provided by Dr. Tao Li from the National Center of Biomedical Analysis (NCBA, Beijing, China). All the experiments were conducted with the appropriate experimental qualifications and were approved by the Ethics Committee of the Fifth Medical Center, the Chinese PLA general hospital. All mice were raised
Psoralidin induces IL-1β maturation and caspase-1 activation
We assessed whether eight active components of PF, namely isobavachin, bavachnin, psoralen, psoralidin, angelicin, bavacholcone, 5-methoxy psoralen, and bavachin, could initiate an immune response by activating inflammasomes (Fig. 1A-B). We first investigated the effect of these compounds on LPS-primed BMDMs following incubation for 6 h. The results demonstrated that only psoralidin induced the secretion of IL-1β, which suggested that it could serve as a direct agonist to induce inflammasome
Discussion
The incidence of IDILI induced by traditional non-toxic Chinese medicine has attracted increasing attention. For clinicians, IDILI is an important factor for ensuring appropriate post-marketing warning and the safe use of medications [28]. The occurrence of IDILI is characterized by stealthiness, contingency, and unpredictability and is independent of the dose of the medication [1]. Clinical and experimental studies have demonstrated that preparations that contain PF, including
CRediT authorship contribution statement
Yan Wang: Conceptualization, Investigation, Methodology, Validation, Writing - original draft. Guang Xu: Conceptualization, Validation, Writing - original draft. Zhilei Wang: Conceptualization, Validation, Writing - original draft. Ruisheng Li: Conceptualization, Validation, Writing - original draft. Xiaoyan Zhan: Methodology, Investigation, Visualization. Hongbin Liu: Visualization, Formal analysis. Qin Qin: Visualization, Formal analysis. Weixia Li: Visualization. Xiaoyan Wang: Visualization.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This study was supported by grants from the Beijing Nova Program (grant number: Z181100006218001), National Natural Science Foundation of China (grant number: 81630100), National Natural Science Foundation of China - Henan Joint Fund (grant number: U1904129), Chinese Postdoctoral Science Foundation (grant number: 2020 M673676), and Postgraduate Scientific Research Innovation Fund Project of Henan University of Chinese Medicine (grant number: 2019KYCX027).
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These authors contributed equally to this work.