CCR2 and CCR5 promote diclofenac-induced hepatotoxicity in mice

Area of Science:

• Immunology
• Hepatology
• Pharmacology

Background:

• Diclofenac (DIC) is a common NSAID associated with significant liver injury.
• The precise immunomolecular mechanisms underlying DIC-induced hepatotoxicity are not fully understood.
• Previous research implicated metabolic factors, oxidative stress, and mitochondrial damage, but immune pathways remain unclear.

Purpose of the Study:

• To investigate the role of chemokine receptors CCR2 and CCR5 in diclofenac-induced liver injury.
• To elucidate the involvement of neutrophil recruitment and TNF-α signaling in this process.
• To explore the therapeutic potential of CCR2 and CCR5 inhibition for DIC hepatotoxicity.

Main Methods:

• Utilized Ccr2, Ccr5, and Tnfr1/2-deficient mice and wild-type littermates.
• Administered diclofenac (DIC) or vehicle for 24 hours.
• Assessed liver injury, hepatic gene expression, neutrophil infiltration, and TNF-α levels.
• Evaluated the effects of CCR2 and CCR5 antagonists.

Main Results:

• Hepatic expression of CCR2, CCR5, and their ligands increased post-DIC treatment.
• DIC-induced liver injury was exacerbated in wild-type mice compared to Ccr2 and Ccr5-deficient mice.
• Blocking CCR2 or CCR5 significantly protected against DIC-induced liver damage and reduced neutrophil recruitment.
• TNF-α levels were lower in Ccr2-deficient mice, and TNF receptor knockout mice showed attenuated hepatotoxicity.

Conclusions:

• CCR2 and CCR5 play a critical role in mediating diclofenac-induced liver injury.
• Neutrophil recruitment, partly mediated by CCR2 and CCR5, contributes to hepatotoxicity.
• TNF-α signaling is involved in the DIC-induced liver damage pathway.
• Pharmacological inhibition of CCR2 or CCR5 presents a promising therapeutic strategy for managing diclofenac hepatotoxicity.