Macrophages Modulate Hepatic Injury Involving NLRP3 Inflammasome: The Example of Efavirenz

Biomedicines

Nadezda Apostolova¹  Miriam Polo¹  Ángeles Álvarez¹  Fernando Alegre¹  Alberto Martí-Rodrigo¹  Juan V. Esplugues¹  Dolores Ortiz-Masiá²  Marcello Pinti³  Celia Bañuls⁴  Ana Blas-García⁴ 

[1] Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain;Departamento de Medicina, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain;Department of Life Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy;Servicio de Endocrinología, FISABIO-Hospital Universitario Dr. Peset, 46017 Valencia, Spain;

关键词: antiviral therapy;    inflammation;    fibrogenesis;    DILI;    macrophage polarization;   

DOI  :  10.3390/biomedicines10010109

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown