Abstract
Drug-induced liver injury (DILI) constitutes a clinical challenge due to the incomplete characterization of the mechanisms involved and potential risk factors. Efavirenz, an anti-HIV drug, induces deleterious actions in hepatocytes that could underlie induction of the NLRP3 inflammasome, an important regulator of inflammatory responses during liver injury. We assessed the potential of efavirenz to modulate the inflammatory and fibrogenic responses of major liver cell types involved in DILI. The effects of efavirenz were evaluated both in vitro and in vivo. Efavirenz triggered inflammation in hepatocytes, in a process that involved NF-κB and the NLRP3 inflammasome, and activated hepatic stellate cells (HSCs), thereby enhancing expression of inflammatory and fibrogenic markers. The NLRP3 inflammasome was not altered in efavirenz-treated macrophages, but these cells polarized towards the anti-inflammatory M2 phenotype and displayed upregulated anti-inflammatory mediators. Conversely, no evidence of damage was observed in efavirenz-treated animals, except when macrophages were depleted, which resulted in the in vivo manifestation of the deleterious effects detected in hepatocytes and HSCs. Efavirenz elicits a cell-specific activation of the NLRP3 inflammasome in hepatocytes and HSCs, but macrophages appear to counteract efavirenz-induced liver injury. Our results highlight the dynamic nature of the interaction among liver cell populations and emphasize the potential of targeting macrophage polarization as a strategy to treat NLRP3 inflammasome-induced liver injury.
Highlights
Dysregulated inflammatory responses contribute to the pathogenesis of most acute and chronic liver diseases, including drug-induced liver injury (DILI), which constitutes a clinical challenge due to the difficulties to characterize the mechanisms involved and the risk factors responsible for its worsening [1]
To assess the specificity of the experiment, EFV (10 μM) -treated extracts were incubated with excess unlabeled primer or mutated probe, which resulted in complete loss of the signal
EFV induced mitochondrial dysfunction in a concentration-dependent fashion, decreasing ΔΨm (TMRM fluorescence) and enhancing the production of reactive oxygen species (ROS). Considered together, these results show that EFV induces a profile of alterations in the functioning of LX2 cells similar to that previously described in hepatocytes (8–11), the former cell line seems to be more resistant to EFV-induced damage
Summary
Dysregulated inflammatory responses contribute to the pathogenesis of most acute and chronic liver diseases, including drug-induced liver injury (DILI), which constitutes a clinical challenge due to the difficulties to characterize the mechanisms involved and the risk factors responsible for its worsening [1]. Excessive inflammation is crucial in drug-induced hepatic damage and, when associated with hepatotoxic insults, it can lead to fibrosis [2]. Hepatic inflammation and fibrogenesis are mediated by the inflammatory pathway regulated by NF-κB and by inflammasomes, intracellular complexes that recognize. Biomedicines 2022, 10, 109 pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) [3,4]. Whose domains include the NOD-like receptor protein 3 (NLRP3), adaptor molecule ASC ( referred to as PYCARD) and serine protease Caspase-1—is the inflammasome most commonly activated in liver diseases [5,6]. We have previously described how efavirenz (EFV), a widely used antiretroviral drug in the treatment of human immunodeficiency virus (HIV) infection, alters the expression of some inflammation-related genes [7] and exhibits a pattern of actions in hepatocytes—it increases
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
