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Macrophages Modulate Hepatic Injury Involving NLRP3 Inflammasome: The Example of Efavirenz
Fernando Alegre1,2, Alberto Martí-Rodrigo1, Miriam Polo1,2
1Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain.
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.
Insights
Efavirenz, an anti-HIV drug, triggers liver injury by activating the NLRP3 inflammasome in hepatocytes and hepatic stellate cells. However, macrophages protect against this injury by adopting an anti-inflammatory M2 phenotype.
Area of Science:
- Hepatology
- Immunology
- Pharmacology
Background:
- Drug-induced liver injury (DILI) mechanisms and risk factors remain incompletely understood.
- Efavirenz, an antiretroviral medication, can cause liver damage, potentially through NLRP3 inflammasome activation.
- The NLRP3 inflammasome is a key regulator of inflammatory responses in liver injury.
Purpose of the Study:
- To investigate how efavirenz affects inflammatory and fibrogenic responses in key liver cell types.
- To explore the role of the NLRP3 inflammasome in efavirenz-induced liver injury.
- To assess the protective or detrimental roles of different liver cell populations in response to efavirenz.
Main Methods:
- In vitro studies using hepatocytes, hepatic stellate cells (HSCs), and macrophages exposed to efavirenz.
- In vivo studies using efavirenz-treated animals, including experiments with macrophage depletion.
- Analysis of inflammatory markers (NF-κB, NLRP3 inflammasome), fibrogenic markers, and macrophage polarization (M2 phenotype).
Main Results:
- Efavirenz induced inflammation in hepatocytes via NF-κB and NLRP3 inflammasome activation.
- Efavirenz activated HSCs, increasing inflammatory and fibrogenic markers.
- Macrophages treated with efavirenz polarized to an anti-inflammatory M2 phenotype, upregulating anti-inflammatory mediators.
- In vivo, efavirenz caused liver damage only when macrophages were depleted, suggesting a protective role.
Conclusions:
- Efavirenz causes cell-specific NLRP3 inflammasome activation in hepatocytes and HSCs, contributing to liver injury.
- Macrophages play a crucial protective role against efavirenz-induced liver injury by counteracting inflammation.
- Targeting macrophage polarization presents a potential therapeutic strategy for DILI involving the NLRP3 inflammasome.
