The carotenoid lutein enhances matrix metalloproteinase-9 production and phagocytosis through intracellular ROS generation and ERK1/2, p38 MAPK, and RARβ activation in murine macrophages

Early studies have demonstrated the ability of dietary carotenoids to enhance immune response, but the mechanism underlying their influence on macrophage activity remains unclear. Here, we investigated the effects of carotenoids on macrophage activity. Carotenoids, including lutein and lycopene, enhanced MMP-9 activity in RAW264.7 macrophages. Lutein was chosen as a representative and analyzed further in this study. It increased the synthesis, activity, and release of MMP-9 in murine RAW264.7 and primary-cultured peritoneal macrophages. MMP-9 induction by lutein was through the transcriptional regulation of mmp-9. It was blunted by the MAPK inhibitors targeting ERK1/2 and p38 MAPK, the reagents that inhibit free radical signaling, and the inhibitors and siRNA targeting RARβ. Moreover, lutein induced Nox activation and intracellular ROS production at an early stage of treatment. This carotenoid also caused ERK1/2 and p38 MAPK activation, RARβ expression, and RAR interaction with its responsive element in the promoter region. These findings suggest the involvement of ROS, MAPKs, and RARβ activation in lutein-driven MMP-9 expression and release. Interestingly, lutein enhanced the phagocytic activity of macrophages, and the secreted MMP-9 appeared to be involved in this process. In summary, we provide evidence here for the first time that the carotenoid lutein induces intracellular ROS generation and MAPK and RARβ activation in macrophages, leading to an increase in MMP-9 release and macrophage phagocytosis. Our results demonstrate that lutein exerts an immunomodulatory effect on macrophages.