Elmo1 Up-regulates Neutrophil Extracellular Trap Formation

Neutrophil extracellular trap(NET)is extracellular structure released by neutrophils in response to infection.NET is a vital strategy to kill pathogens,and ROS is demonstrated as an important element for NET formation,but the molecular pathways governing NET formation are not well understood.There are studies showing that Dock plays a critial role in NET formation,yet the understanding of the molecular mechanism by which regulates Dock remains unknown.Considering that Engulfment and cell motility 1(Elmo1)and Dock functions a complex,our aim of this study was to investigate the role of Elmo1 in the process of NET formation.We found that PMAinduced reactive oxygen species(ROS)production and NET formation were significantly reduced in Elmo1 KO neutrophils.Meantime,the differences in NET formation between wild-type and Elmo1 KO mice disappeared after using antioxidant NAC.Thus,we can conclude that Elmo1 up-regulates the formation of NET by influencing ROS production.Further research of the molecular mechanism revealed that Elmo1 promote NET formation through up-regulating the activation of p38 and Akt.Due to the fact that Elmo1 interacts with Dock as a guanine nucleotide exchange factor(GEF)to activate Rac and Rac plays an important role in ROS production,we examined the role of Rac in Elmo1-regulating ROS production and NET formation in neutrophils.Our results show that Elmo1 promotes Rac activation to increase ROS production and NET formation.At the same time,the activation of p38 and Akt is enhanced through Rac.In summary,Elmo1 promotes ROS production and activation of p38 and Akt through Rac activation,and finally contributes to NET formation.Thus,our research provides a new theoretical basis for treating NET-associated diseases in neutrophils.