Inhibition of cathepsin L ameliorates inflammation through the A20/NF-κB pathway in endotoxin-induced acute lung injury

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a severe inflammatory condition that remains refractory; however, its molecular mechanisms are largely unknown. Previous studies have shown numerous compounds containing 4-indolyl-2-aminopyrimidine that display strong anti-inflammatory properties. In our research, we identified that a 4-Indole-2-Arylaminopyrimidine derivative named "IAAP" suppressed lipopolysaccharide (LPS)-induced inflammation. Immunoprecipitation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified that IAAP interacts with a lysosomal cysteine protease, cathepsin L (CTSL), and restrains its activity. The nuclear factor kappa B (NF-κB) family plays a central role in controlling innate immunity. Canonical NF-κB activation, such as stimulation with lipopolysaccharide (LPS), typically involves the degradation of A20. We observed that IAAP suppression of CTSL prevented the LPS-induced degradation of A20, thereby ameliorating NF-κB activation. This study identifies CTSL as a crucial regulator of A20/NF-κB signaling and suggests IAAP as a potential lead compound for developing drugs to treat ALI/ARDS.

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Publication Details

Journal
iScience
Published
2024-10-04
DOI
https://doi.org/10.1016/j.isci.2024.111024
Citations
10
Primary Topic
Inflammasome and immune disorders
Type
article
Field-Weighted Citation Impact
2.34

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article

Inhibition of cathepsin L ameliorates inflammation through the A20/NF-κB pathway in endotoxin-induced acute lung injury

Zhouyang Li, Fugui Yan, Zhengtong Mao, Huahao Shen et al.
10 citations
iScience
Inflammasome and immune disorders
2.34
article

Inhibition of cathepsin L ameliorates inflammation through the A20/NF-κB pathway in endotoxin-induced acute lung injury

Zhouyang Li, Fugui Yan, Zhengtong Mao, Huahao Shen, Xingxian Zhang, Yun Zhao, Shiyi Yang, Nanxia Xuan, Tianpeng Chen, Yang Yu, Kaijun Chen, Songmin Ying, Zhangchu Jin, Wen Li, Min Zhang, Fei Xia, Zhihua Chen, Yinfang Wu, Gensheng Zhang, Na Li, Baoping Tian, Jinkang Yu, Wenbing Wang
article en
10 citations

Abstract

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a severe inflammatory condition that remains refractory; however, its molecular mechanisms are largely unknown. Previous studies have shown numerous compounds containing 4-indolyl-2-aminopyrimidine that display strong anti-inflammatory properties. In our research, we identified that a 4-Indole-2-Arylaminopyrimidine derivative named "IAAP" suppressed lipopolysaccharide (LPS)-induced inflammation. Immunoprecipitation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified that IAAP interacts with a lysosomal cysteine protease, cathepsin L (CTSL), and restrains its activity. The nuclear factor kappa B (NF-κB) family plays a central role in controlling innate immunity. Canonical NF-κB activation, such as stimulation with lipopolysaccharide (LPS), typically involves the degradation of A20. We observed that IAAP suppression of CTSL prevented the LPS-induced degradation of A20, thereby ameliorating NF-κB activation. This study identifies CTSL as a crucial regulator of A20/NF-κB signaling and suggests IAAP as a potential lead compound for developing drugs to treat ALI/ARDS.

iScienceVol. 27(11)
State Key Laboratory of Respiratory Disease (CN), Second Affiliated Hospital of Zhejiang University (CN), Zhejiang University of Technology (CN), Zhejiang University (CN)
National Natural Science Foundation of China, Zhejiang University, Natural Science Foundation of Zhejiang Province
Good health and well-being
Openalex Percentile: Top 11%
Inflammasome and immune disorders
2.34
DOIOpen Access PDFOpenAlex
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