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The role of NLRP3 inflammasome in psychotropic drug-induced hepatotoxicity.

ABSTRACT: Increased medical application of psychotropic drugs raised attention concerning their toxicological effects. In fact, more than 160 psychotropic drugs including antidepressants and antipsychotics, have been shown to cause liver side effects, but the underlying mechanisms are still poorly understood. Here, we discovered that fluoxetine, a common antidepressant, was specifically sensed by NLRP3 inflammasome, whose subsequent activation resulted in the maturation of caspase-1 and IL-1β, as well as gasdermin D (GSDMD) cleavage, which could be completely abrogated by a selective NLRP3 inhibitor MCC950 or Nlrp3 knockout (Nlrp3^-/-). Mechanistically, mitochondrial damage and the subsequent mitochondrial reactive oxygen species (mtROS) accumulation were crucial upstream signaling events in fluoxetine-triggered NLRP3 inflammasome activation. In fluoxetine hepatotoxicity models, mice showed the alterations of aminotransferase levels, hepatic inflammation and hepatocyte death in an NLRP3-dependent manner, and MCC950 pretreatment could reverse these side effects of fluoxetine. Notably, we also found that multiple antidepressants, such as amitriptyline, paroxetine, and imipramine, and antipsychotics, such as asenapine, could specifically trigger the NLRP3 inflammasome activation. Collectively, our findings implicate multiple psychotropic drugs may act as danger signals sensed by the NLRP3 inflammasome and result in hepatic injury.

SUBMITTER: Mu W

PROVIDER: S-EPMC9271040 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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The role of NLRP3 inflammasome in psychotropic drug-induced hepatotoxicity.

Mu Wenqing W Xu Guang G Wei Ziying Z Wang Zhilei Z Qin Qin Q Lin Li L Ren Lutong L Liu Tingting T Fang Zhie Z Yang Yan Y Zhao Jing J Wang Junnan J Zhan Xiaoyan X Xiao Xiaohe X Bai Zhaofang Z

Cell death discovery 20220709 1

Increased medical application of psychotropic drugs raised attention concerning their toxicological effects. In fact, more than 160 psychotropic drugs including antidepressants and antipsychotics, have been shown to cause liver side effects, but the underlying mechanisms are still poorly understood. Here, we discovered that fluoxetine, a common antidepressant, was specifically sensed by NLRP3 inflammasome, whose subsequent activation resulted in the maturation of caspase-1 and IL-1β, as well as ...[more]

PMID: 35810159

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Project description:BackgroundEpimedii Folium (EF) is commonly used for treating bone fractures and joint diseases, but the potential hepatotoxicity of EF limits its clinical application. Our previous study confirms that EF could lead to idiosyncratic drug-induced liver injury (IDILI) and hepatocyte apoptosis, but the mechanism remains unknown. Studies have shown that NLRP3 inflammasome plays an important role in the development of various inflammatory diseases such as IDILI. Specific stimulus-induced NLRP3 inflammasome activation may has been a key strategy for lead to liver injury. Therefore, main compounds derived from EF were chosen to test whether the ingredients in EF could activate the NLRP3 inflammasome and to induce IDILI.MethodsBone-marrow-derived macrophages (BMDMs) were treated with Icariside I, and then stimulated with inflammasome stimuli and assayed for the production of caspase-1 and interleukin 1β (IL-1β) and the release of lactate dehydrogenase (LDH). Determination of intracellular potassium, ASC oligomerization as well as reactive oxygen species (ROS) production were used to evaluate the stimulative mechanism of Icariside I on inflammasome activation. Mouse models of NLRP3 diseases were used to test whether Icariside I has hepatocyte apoptosis effects and promoted NLRP3 inflammasome activation in vivo.ResultsIcariside I specifically enhances NLRP3 inflammasome activation triggered by ATP or nigericin but not SiO2, poly(I:C) or cytosolic LPS. Additionally, Icariside I does not alter the activation of NLRC4 and AIM2 inflammasomes. Mechanically, Icariside I alone does not induce mitochondrial reactive oxygen species (mtROS), which is one of the critical upstream events of NLRP3 inflammasome activation; however, Icariside I increases mtROS production induced by ATP or nigericin but not SiO2. Importantly, Icariside I leads to liver injury and NLRP3 inflammasome activation in an LPS-mediated susceptibility mouse model of IDILI, but the effect of Icariside I is absent in the LPS-mediated mouse model pretreated with MCC950, which is used to mimic knockdown of NLRP3 inflammasome activation.ConclusionsOur study reveals that Icariside I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity. The findings suggest that Icariside I or EF should be avoided in patients with diseases related to ATP or nigericin-induced NLRP3 inflammasome activation, which may be risk factors for IDILI. Video abstract.

Project description:Background: Doxorubicin (DOX) has been widely used in cancer treatment. However, DOX can cause a range of significant side effects, of which hepatotoxicity is a common one, and therefore limits its clinical use. Pterostilbene (PTS) has been shown to exhibit anti-oxidant and anti-inflammatory effects in the treatment of liver diseases but whether PTS could protect against hepatotoxicity in DOX-treated mice is unknown. Methods: In our study, we use C57/BL6J mice and the HepG2 cell line. We divided the mice in 4 groups: the control, the PTS treatment, the DOX treatment, and the DOX + PTS treatment group. Liver histopathology was judged by performing hematoxylin-eosin and Masson staining. Immunohistochemistry was used to perform the expression of NLRP3. The levels of serum alanine transaminase (ALT) and aspartate transaminase (AST) were evaluated. Levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and DCFH-DA staining were used to evaluate the oxidative injury. Western blot and real-time PCR were applied to evaluate the expressions of proteins and mRNA. MTT was used to evaluate DOX-induced cell injury and the protective effects of PTS. Recombinant Trx-1 was used to analyze the mechanism of PTS. A TUNEL assay was used to detect apoptosis in DOX-induced HepG2 cells and the protective effects of PTS. Results: PTS ameliorated DOX-induced liver pathological changes and the levels of AST and ALT. PTS also decreased the level of MDA, increased the level of SOD, GSH, and the expression of Trx-1 in DOX-treated mice. PTS decreased the levels of NLRP3 and IL-1β mRNA and the expressions of their proteins in DOX-treated mice. In addition, PTS also decreased the expression of Cleaved Caspase-3 and BAX and increased the expression of BCL-2. In vitro, after treatment with recombinant Trx-1, ROS and NLRP3 inflammasome were both decreased. Treatment with PTS could rescue the downregulation of Trx-1, decreased the ROS level and the NLRP3 inflammasome, and protected HepG2 cells against DOX-induced apoptosis. Conclusion: The results show that PTS exhibits protective effects against DOX-induced liver injuries via suppression of oxidative stress, fibrosis, NLRP3 inflammasome stimulation, and cell apoptosis which might lead to a new approach of preventing DOX-induced hepatotoxicity.

Project description:BackgroundGlucocorticoid-induced transcript 1 (GLCCI1) has been reported to be associated with the efficiency of inhaled glucocorticoids in patients with asthma. This study aimed to investigate the role of GLCCI1 in the regulation of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) by the phosphatidylinositol 3-kinase (PI3K) pathway in the pathogenesis of allergic asthma.MethodsThe expression levels of genes encoding GLCCI1, NLRP3 inflammasome components, and PI3K pathway-related indicators were detected in cells isolated from induced sputum from patients with asthma and healthy controls. Next, we induced asthma in wild-type C57BL/6 mice and Glcci1 knockout (Glcci1 -/-) mice by injecting them with ovalbumin (OVA) and treated the asthmatic mice with a PI3K pathway inhibitor (LY294002) or left them untreated. We also performed adoptive transfer of macrophages into the mice and assessed lung inflammation, as well as GLCCI1, PI3K pathway component, and NLRP3 inflammasome component expression levels. Finally, primary bone marrow-derived macrophages (BMDMs) from wild-type and Glcci1 -/- mice were treated with OVA, either in the presence or absence of LY294002 and the NLRP3 inhibitor (MCC950), to validate our findings.ResultsThe mRNA level of Glcci1 in induced sputum cells from asthmatic patients was lower compared to that of healthy controls. Additionally, Glcci1 mRNA expression correlated negatively with NLRP3 inflammasome indicators and the PI3K pathway components, as well as with IL-1β expression in induced sputum macrophages. In vivo, Glcci1 -/- asthmatic mice showed elevated levels of airway inflammation and NLRP3 inflammasome activation compared to wild-type asthmatic mice. Surprisingly, the efficacy of LY294002 in reducing lung tissue inflammation and NLRP3 inflammasome activity in wild-type asthmatic mice was attenuated by Glcci1 knockout. LY294002 enhanced GLCCI1 levels in macrophages within the lung tissue of wild-type asthmatic mice. Moreover, LY294002 did not inhibit lung inflammation in wild-type asthmatic mice depleted of macrophages that had received adoptive transfer of Glcci1 -/- BMDMs. In vitro experiments further illustrated that LY294002 suppressed NLRP3 activation by upregulating GLCCI1 expression in BMDMs. The introduction of MCC950 led to a marked decrease in NLRP3 and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) protein levels, but did not affect the expression levels of GLCCI1 or the phospho-protein kinase B (p-AKT)/AKT ratio.ConclusionsGLCCI1 deficiency promotes asthma inflammation through PI3K-induced NLRP3 inflammasome activation.

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The role of NLRP3 inflammasome in psychotropic drug-induced hepatotoxicity.

Publications

The role of NLRP3 inflammasome in psychotropic drug-induced hepatotoxicity.

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