CCR2 and CCR5 promote diclofenac-induced hepatotoxicity in mice
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Liver injury, one of the major side effects of diclofenac (DIC), plagues thousands of patients who treated with it. Although involvements of metabolic factors, oxidative stress, and mitochondrial injury have been characterized, the exact immunomolecular mechanism of the hepatotoxicity of DIC still remains ambiguous. In this study, we investigated the role of chemokine receptors CCR2 and CCR5 in this progression. Ccr2, Ccr5, and Tnfr1/2-deficient mice, as well as wild type littermates, were administrated DIC or vehicle for 24 h, receptively. Hepatic expression of CCR2, CCR5, and their ligands were upregulated after DIC treatment. DIC-induced liver injury was augmented in Ccr2+/+ mice than Ccr2−/− mice, a similar phenotype was observed in Ccr5-deficient mice. In addition, antagonists of CCR2 or CCR5 protected liver damage caused by diclofenac. Besides, the number of neutrophils present in the liver was gradually increased from 0 to 12 h after drug administration. However, the recruitment of neutrophils was dramatically lessened after blocking CCR2 or CCR5 signaling. Furthermore, TNF-α level in the liver was decreased in Ccr2−/− mice compared with Ccr2+/+ mice. Intriguingly, in line with this, TNF receptor 1 and 2 double knockout mice showed markedly attenuated hepatotoxicity of DIC. These suggested that CCR2 and CCR5 mediated hepatotoxicity induced by diclofenac, TNF-α was responsible, at least in part, for it, and the pharmacological inhibition of CCR2 or CCR5 might serve as a novel therapeutic approach for DIC-induced hepatotoxicity.
KeywordsDiclofenac Acute liver injury CCR2 CCR5 Neutrophils TNF-α
Author contribution statement
ZH, GW, NL, MN, and SG conducted experiments. YJ and PC conceived and designed the research. GW and TW analyzed the data. ZH, GW, and PC wrote the manuscript. All authors read and approved the manuscript.
This study was supported in part by the Natural Science Funds for Distinguished Young Scholar of Guangdong province (2016A030306043), the award of Young Pearl Scholars of Guangdong province, and the funding from State Key Laboratory of Organ Failure Research (201804) to PC. The Grant of NSFC-Guangdong Joint Foundation of China (U1601225), National Natural Science Foundation of China (81372030), and Key Scientific and Technological Program of Guangzhou City (201607020016) to JY.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All experiments were performed according to the National Institutes of Health guidelines and were approved by the Southern Medical University Experimental Animal Ethics Committee.
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