Hepatic ROS Mediated Macrophage Activation Is Responsible for Irinotecan Induced Liver Injury

Irinotecan is the first line chemotherapy drug used for treatment of metastatic colorectal cancer worldwide. There is increasing evidence suggesting that liver damage, including steatosis and steatohepatitis, can be caused during the treatment involving irinotecan. However, molecular mechanisms by which irinotecan-induced liver injury remain elusive. In this study, we found that irinotecan treatment caused significant elevation of ALT, inflammation, and fat accumulation in the liver, which are associated with hepatic macrophage activation. Depletion of macrophages by clodronate liposome improved irinotecan induced liver injury and inflammatory response in mice. In vitro data indicated that irinotecan induced intracellular ROS production in primary hepatocyte and upregulating of toll-like receptor (TLRs) family expression in macrophages. Supernatant from irinotecan treated hepatocyte triggered macrophage activation and upregulation of TLRs in macrophage, and N-acetylcysteine (NAC) abolished these effects. By using co-culture system, we further revealed that irinotecan activated macrophage induced impairment of lipid metabolism and promoted apoptosis in hepatocyte and NAC prevented macrophage-induced cell death and partially revered impaired lipid metabolism in hepatocytes. By using the irinotecan liver injury model, we demonstrated that combining NAC with irinotecan prevented irinotecan-induced macrophage activation, TLR upregulation, liver injury, and partially prevented the accumulation of triglycerides in liver. Our results thus indicated that macrophages play a critical role in irinotecan-induced liver injury, and targeting ROS provides new options for development of hepatoprotective drugs in clinical practice.

Automated summary

Irinotecan, a chemotherapy drug used for metastatic colorectal cancer treatment, can cause liver damage including steatosis and steatohepatitis. In this study, it was found that irinotecan treatment elevated ALT levels, inflammation, and fat accumulation in the liver, which were associated with macrophage activation. Depletion of macrophages improved irinotecan-induced liver injury and inflammatory response. In vitro experiments showed that irinotecan induced ROS production in hepatocytes and upregulated toll-like receptor (TLRs) expression in macrophages. Supernatant from irinotecan-treated hepatocytes triggered macrophage activation and upregulation of TLRs, which were abolished by N-acetylcysteine (NAC). Co-culture experiments revealed that irinotecan-activated macrophages impaired lipid metabolism and induced hepatocyte apoptosis, which were partially prevented by NAC. Using a liver injury model, the combination of NAC and irinotecan prevented macrophage activation, TLR upregulation, liver injury, and triglyceride accumulation.