Dissecting The Role Of ROS-induced FABP5 S-glutathionylation In Macrophage-mediated Hyperoxia-induced Lung Injury

Although oxygen is used as a therapy improving outcome following a variety of diseases,it can also induce some injuries,especially,hyperoxia-induced lung injury,which becomes a limiting factor in its clinical application.Hyperoxia-induced lung injury is most closely related to oxidative stress,but its internal molecular regulatory mechanisms are various and still need further study.Increased cellular oxidative stress promotes protein-S-glutathionylation in a variety of proteins.Protein-S-glutathionylation is a reversible post-translational modification that continues to achieve eminence as a redox regulatory mechanism of cellular signaling pathway and protein activity.In addition,the de-glutathionylation of proteins is specifically catalyzed by glutaredoxin-1(Grx1).Nevertheless,the in vivo function of protein-S-glutathionylation in hyperoxia-induced lung injury remains unclear.In this study,we firstly found that absence of Grx1 significantly ameliorated hyperoxia-induced lung injury.Additionally,macrophages were most sensitive to oxidative stress in various cell types.And protein-S-glutathionylation was significantly increased in alveolar macrophages of hyperoxia-induced lung injury mice with Grx1 deficiency,according to which we speculated that macrophages played an important role in the pathogenesis of hyperoxia-induced lung injury.According to the results of quantitative mass spectrometry screening and in vitro experiments,we demonstrated that oxidative stress led to an increase in FABP5-SSG level of macrophage.And this modification was accompanied by the formation of FABP5 dimers and oligomers.FABP5 is a small molecular mass intracellular lipid chaperone that is involved in a variety of biological processes,including fatty acid uptake,fatty acid transport,metabolism and inflammatory regulation.Mechanistically,we found that the glutathionylation of FABP5 promoted its fatty acid binding abilities.In the presence of an activating ligand(such as,fatty acids),FABP5 was imported into the nucleus where it directly delivered the ligand to PPAR?/?,thus activating PPAR?/? and inhibiting macrophage inflammation.Further analysis showed that FABP5 C127 S inhibited FABP5's glutathionylation,fatty acid binding ability,nuclear translocation and function of inflammation regulation in macrophage.In conclusion,loss of Grx1 and increased protein-S-glutathionylation attenuate hyperoxia-induced lung injury in mice,glutathionylation of the Cys-127 in FABP5 serves an anti-inflammatory function in ROS-induced macrophage inflammation during this process,providing a theoretical and practical basis for effective use of oxygen therapy and lung injury reduction.