Abstract
Oxidative stress contributes to the pathogenesis of acute lung injury. Protein S-glutathionylation plays an important role in cellular antioxidant defense. Here we report that the expression of deglutathionylation enzyme Grx1 is decreased in the lungs of acute lung injury mice. The acute lung injury induced by hyperoxia or LPS is significantly relieved in Grx1 KO and Grx1fl/flLysMcre mice, confirming the protective role of Grx1-regulated S-glutathionylation in macrophages. Using a quantitative redox proteomics approach, we show that FABP5 is susceptible to S-glutathionylation under oxidative conditions. S-glutathionylation of Cys127 in FABP5 promotes its fatty acid binding ability and nuclear translocation. Further results indicate S-glutathionylation promotes the interaction of FABP5 and PPARβ/δ, activates PPARβ/δ target genes and suppresses the LPS-induced inflammation in macrophages. Our study reveals a molecular mechanism through which FABP5 S-glutathionylation regulates macrophage inflammation in the pathogenesis of acute lung injury.
Highlights
Oxidative stress contributes to the pathogenesis of acute lung injury
We found that S-glutathionylation promotes the fatty-acid binding and nuclear translocation of FABP5, activating PPARβ/δ and suppressing macrophage inflammation
reactive oxygen species (ROS) plays a pivotal role in physiological cellular processes, but the generation of excess ROS causes oxidative damage to molecules and cells in a multitude of pathological conditions, including acute lung injury[50]
Summary
Oxidative stress contributes to the pathogenesis of acute lung injury. Protein S-glutathionylation plays an important role in cellular antioxidant defense. The acute lung injury induced by hyperoxia or LPS is significantly relieved in Grx[1] KO and Grx1fl/flLysMcre mice, confirming the protective role of Grx1-regulated S-glutathionylation in macrophages. Our study reveals a molecular mechanism through which FABP5 S-glutathionylation regulates macrophage inflammation in the pathogenesis of acute lung injury. Redox regulation of cell function often involves the conversion of reactive thiols on specific cysteine residues from reduced to oxidized forms. The major types of thiol modification that have been shown to play an important redox-dependent role include protein S-glutathionylation, sulfenic acid formation, nitrosylation, and disulfide bond formation[2]. In many types of cells, oxidative stress has been shown to drive the S-glutathionylation of free thiol groups (-SH) on the cysteine residues of proteins to form protein-glutathione mixed disulfide adducts (Pr-SSG). It is becoming increasingly evident that protein S-glutathionylation and Grx[1] perform a wide range of antioxidant, anti-inflammatory, and anti-apoptotic functions in the body, participating in acute and chronic inflammatory responses[19,20]
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