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Destabilization of Lysophosphatidic Acid Receptor 1 Reduces Cytokine Release and Protects Against Lung Injury.

ABSTRACT: Lysophosphatidic acid receptor 1 (LPA1) is a druggable target for treating pulmonary inflammatory diseases. However, the molecular regulation of LPA1 stability, a factor that critically impacts its biological activity, remains largely unknown. Here we identify two enzymes that regulate the balance of LPA1 ubiquitination and deubiquitination. Ubiquitin E3 ligase Nedd4L targets LPA1 for its site specific ubiquitination and degradation in the lysosome. Nedd4L negatively regulates LPA-LPA1-mediated cytokine release. The stability of LPA1 is up-regulated by ubiquitin-specific protease 11 (USP11), which deubiquitinates LPA1 and enhances LPA1-mediated pro-inflammatory effects. LPA1 is associated with USP11 in quiescent cells, while LPA treatment triggers LPA1 dis-association with USP11 and in turn binding to Nedd4L. Knockdown or inhibition of USP11 reduces LPA1 stability, levels of LPA1, and LPA1-CD14 interaction complex; thereby diminishing both LPA- and LPS-induced inflammatory responses and lung injury in preclinical murine models. Thus, our findings identify an ubiquitin E3 ligase and a deubiquitinating enzyme responsible for regulation of LPA1 stability and biological activities. This study provides potential targets for the development of anti-inflammatory molecules to lessen lung injury.

SUBMITTER: Zhao J

PROVIDER: S-EPMC5006730 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Destabilization of Lysophosphatidic Acid Receptor 1 Reduces Cytokine Release and Protects Against Lung Injury.

Zhao Jing J Wei Jianxin J Dong Su S Bowser Rachel K RK Zhang Lina L Jacko Anastasia M AM Zhao Yutong Y

EBioMedicine 20160718

Lysophosphatidic acid receptor 1 (LPA1) is a druggable target for treating pulmonary inflammatory diseases. However, the molecular regulation of LPA1 stability, a factor that critically impacts its biological activity, remains largely unknown. Here we identify two enzymes that regulate the balance of LPA1 ubiquitination and deubiquitination. Ubiquitin E3 ligase Nedd4L targets LPA1 for its site specific ubiquitination and degradation in the lysosome. Nedd4L negatively regulates LPA-LPA1-mediated ...[more]

PMID: 27448760

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Project description:Salvianolic acid A (SAA) is one of bioactive polyphenol extracted from a Salvia miltiorrhiza (Danshen), which was widely used to treat cardiovascular disease in traditional Chinese medicine. SAA has been reported to be protective in cardiovascular disease and ischemia injury, with anti-inflammatory and antioxidative effect, but its role in acute lung injury (ALI) is still unknown. In this study, we sought to investigate the therapeutic effects of SAA in a murine model of lipopolysaccharide- (LPS-) induced ALI. The optimal dose of SAA was determined by comparing the attenuation of lung injury score after administration of SAA at three different doses (low, 5 mg/kg; medium, 10 mg/kg; and, high 15 mg/kg). Dexamethasone (DEX) was used as a positive control for SAA. Here, we showed that the therapeutic effect of SAA (10 mg/kg) against LPS-induced pathologic injury in the lungs was comparable to DEX. SAA and DEX attenuated the increased W/D ratio and the protein level, counts of total cells and neutrophils, and cytokine levels in the BALF of ALI mice similarly. The oxidative stress was also relieved by SAA and DEX according to the superoxide dismutase and malondialdehyde. NET level in the lungs was elevated in the injured lung while SAA and DEX reduced it significantly. LPS induced phosphorylation of Src, Raf, MEK, and ERK in the lungs, which was inhibited by SAA and DEX. NET level and phosphorylation level of Src/Raf/MEK/ERK pathway in the neutrophils from acute respiratory distress syndrome (ARDS) patients were also inhibited by SAA and DEX in vitro, but the YEEI peptide reversed the protective effect of SAA completely. The inhibition of NET release by SAA was also reversed by YEEI peptide in LPS-challenged neutrophils from healthy volunteers. Our data demonstrated that SAA ameliorated ALI via attenuating inflammation, oxidative stress, and neutrophil NETosis. The mechanism of such protective effect might involve the inhibition of Src activation.

Dataset Information

Destabilization of Lysophosphatidic Acid Receptor 1 Reduces Cytokine Release and Protects Against Lung Injury.

Publications

Destabilization of Lysophosphatidic Acid Receptor 1 Reduces Cytokine Release and Protects Against Lung Injury.

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