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

Yuxian Guo; Yaru Liu; Shihao Zhao; Wangting Xu; Yiqing Li; Pengwei Zhao; Di Wang; Hongqiang Cheng; Yuehai Ke; Xue Zhang

doi:10.1038/s41467-021-27428-9

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

Nat Commun. 2021 Dec 7;12(1):7094. doi: 10.1038/s41467-021-27428-9.

Authors

Yuxian Guo^#^{1

2}, Yaru Liu^#¹, Shihao Zhao¹, Wangting Xu¹, Yiqing Li¹, Pengwei Zhao³, Di Wang², Hongqiang Cheng^{1

4}, Yuehai Ke^{5

6

7}, Xue Zhang^{8

9}

Affiliations

¹ Department of Pathology and Pathophysiology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, P.R. China.
² Institute of Immunology, Zhejiang University School of Medicine, 310058, Hangzhou, P.R. China.
³ Department of Biochemistry, Zhejiang University School of Medicine, 310058, Hangzhou, P.R. China.
⁴ Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, P.R. China.
⁵ Department of Pathology and Pathophysiology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, P.R. China. yke@zju.edu.cn.
⁶ Department of Respiratory Medicine of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, P.R. China. yke@zju.edu.cn.
⁷ Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, 311121, Hangzhou, China. yke@zju.edu.cn.
⁸ Department of Pathology and Pathophysiology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, P.R. China. zhangxue@zju.edu.cn.
⁹ Department of Respiratory Medicine of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, P.R. China. zhangxue@zju.edu.cn.

^# Contributed equally.

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 Grx1^fl/flLysM^cre 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Lung Injury / drug therapy*
Acute Lung Injury / metabolism
Acute Lung Injury / pathology
Animals
Fatty Acid-Binding Proteins / genetics
Fatty Acid-Binding Proteins / metabolism*
Gene Expression Regulation
Glutaredoxins / genetics
Glutaredoxins / metabolism
Hyperoxia
Inflammation*
Lung / pathology
Macrophages
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neoplasm Proteins / genetics*
Neoplasm Proteins / metabolism*
Oxidation-Reduction
Oxidative Stress*
Protective Agents / pharmacology*
Protein Processing, Post-Translational
Recombinant Proteins

Substances

Fabp5 protein, mouse
Fatty Acid-Binding Proteins
Glrx protein, mouse
Glutaredoxins
Neoplasm Proteins
Protective Agents
Recombinant Proteins