Macrophage Maintains Redox Homeostasis And Prevents Cellular Aging Through Mst1/2-Keap1-Nrf2 Axis

Reactive oxygen species(ROS)plays an important role in the innate immune system,especially in macrophages.It has been reported that ROS assist macrophages to eliminate harmful microorganisms engulfed into the cell.Nevertheless,excessive ROS can cause oxidative damage to cellular components including DNA,lipids and proteins,even worse lead the cellular aging and cell death.Therefore,it is crucial for macrophages to maintain redox homeostasis,however,the underlying mechanism still remains to be determined.The kinases Mstl and Mst2,the core kinases of the Hippo signaling pathway,have been previously shown to regulate cell proliferation and promote apoptosis during tissue development and regeneration.Recently,ourlab reported that Mst1 and Mst2 were important for the bactericidal activity of phagocytes by promoting the induction of ample amount of phagosomal ROS and mitochondrial ROS(mROS).Here we continue to demonstrate that kinases Mstl/2 acted as a sensor of intracellular ROS,and by regulating the protein stability of transcription factor Nrf2,eliminated excessive reactive oxygen species and consequently protected macrphages from oxidative damage.Brefly,during the oxidative stress,activated Mstl/2 stabilize Nrf2 by phosphorylating E3 ligase Keapl to prevent its polymerization and subsequently dissociate the Keap1/Nrf2 complex,thereby failing to target Nrf2 for degradation.In conclusion,our resulted showed that Mstl/2-Keap1-Nrf2 axis plays a pivotal role in macrophage ROS homeostasis.