Oxidative stress-induced FABP5 S-glutathionylation protects against acute lung injury by suppressing inflammation in macrophages

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.

Macrophage Polarization and Reprogramming in Acute Inflammation: A Redox Perspective

“…Glutaredoxin (GRX) 1, a thiol-disulfide oxidoreductase that specifically catalyzes the reduction of S-glutathionylated substrates, is known to be a regulator of inflammatory disease models [ 170 , 171 ]. Remarkably, Guo et al have demonstrated that macrophage-specific Grx1 deficiency alleviates acute lung injury inflammation [ 172 ]. In their work, ROS induce S-glutathionylation of fatty acid binding protein (FABP5) in macrophages, which increases nuclear FABP5 levels, activates PPARβ/δ, and abrogates inflammation in the macrophages incubated with LPS [ 172 ].…”

Effect of RNAi Targeting SeGrx1 on the Cytotoxicity and Insecticide Susceptibility of Camptothecin in Spodoptera exigua

“…Our results suggested that the inhibition effect on the growth of CPT can be increased by the knocking down of SeGrx1, which showed that CPT as an insecticide may be used with other insecticides for enhanced efficiency in controlling important insect pests in the field. In Homo sapiens, Grxs have been implicated in various physiological and pathological conditions, from immune defense to neurodegeneration and cancer development, which makes Grxs a possible drug target [8,31]. The RNAi-mediated gene knockdown has shown promising results in different insect groups, pointing it to be the upcoming technique for insect control [32][33][34][35][36].…”

“…Grx1 can play the regulatory roles through both its enzymatic redox activity and protein-protein interactions with specific proteins, such as Ask1, Ras, Fas, and procaspase-3, which are involved in the apoptosis signal transduction pathway [7]. It has been proved by a growing body of evidence that there is potential clinical and therapeutic application of Grx1 in atherosclerosis, and neurodegenerative disease, and aging-related diseases [8].…”

Thiol Modifications in the Extracellular Space—Key Proteins in Inflammation and Viral Infection

“…S-glutathionylation is the formation of a disulfide bond between the thiol group of GSH and a protein ( 77 ), catalyzed by Grxs ( 78 ). Intracellular proteins that can be glutathionylated include actin (Cys374) ( 79 ), Fatty Acid Binding Protein 5 ( 80 ), Major vault protein ( 81 ), NFκB ( 82 , 83 ), sarco/endoplasmic reticulum Ca 2+ -ATPase (Cys674) ( 84 ), Signal transducer and activator of transcription 1 (STAT1) (Cys324 and Cys492) ( 39 , 85 ), STAT3 (Cys328 and Cys542) ( 85 ), and members of the Trx family ( 17 , 86 , 87 ). Glutathionylation is crucial for signaling pathways and cellular processes like proliferation, differentiation, apoptosis, cytokine production ( 76 ), and metabolic changes in response to inflammatory signals ( 88 ).…”