Targeting ERK1/2 attenuates neutrophil extracellular traps-mediated pro-inflammatory and pro-fibrotic effects in
Hui Chai1, Jumei Yang2, Wenjun Li1
1The Second Clinical Medical College, Lanzhou University, Lanzhou, China.
Objective:
This study aimed to investigate the mechanism and therapeutic potential of targeting the extracellular signal-regulated kinase 1/2 (ERK1/2) signalling pathway in myositis-associated interstitial lung disease, focusing on its role in neutrophil extracellular traps (NETs)-mediated pro-inflammatory and pro-fibrotic processes.
Methods:
Lung tissue samples were collected from patients with idiopathic inflammatory myopathy-associated ILD (IIM-ILD) and from mice with experimental autoimmune myositis (EAM) and a myositis-associated interstitial lung disease model (MAILD). Multiple experimental techniques, including immunohistochemistry, western blotting, immunofluorescence and transcriptome sequencing were employed to analyse ERK1/2 activation, NETs infiltration and the expression of epithelial-mesenchymal transition (EMT)-related markers. The ERK1/2 inhibitor U0126 was applied both in vivo and in vitro for interventional validation.
Results:
The ERK1/2 signalling pathway was activated in the lung tissues of IIM-ILD patients and in the EAM and MAILD mouse models. Substantial NETs infiltration was observed in the lung tissues of EAM and MAILD mice. NETs induced EMT and the release of pro-inflammatory factors by activating ERK1/2. Inhibiting NETs formation attenuated ERK1/2 phosphorylation and the downstream fibrotic process. Administration of the ERK1/2 inhibitor U0126 not only effectively alleviated NETs-induced EMT and inflammatory responses but also significantly reduced pulmonary inflammation infiltration and NETs formation in the MAILD model.
Conclusion:
NETs-mediated pro-inflammatory and pro-fibrotic processes contribute to the progression of myositis-associated interstitial lung disease by activating the ERK1/2 signalling pathway. Targeting ERK1/2 effectively inhibits this pathogenic cascade, providing a novel strategy for clinical treatment.
Insights
Neutrophil Extracellular Traps (NETs) drive inflammation and fibrosis in myositis-associated interstitial lung disease by activating the ERK1/2 pathway. Targeting ERK1/2 offers a promising new treatment strategy for this condition.
Area of Science:
- Pulmonary Medicine
- Immunology
- Cellular Signaling
Background:
- Interstitial lung disease (ILD) is a severe complication of Idiopathic Inflammatory Myopathy (IIM).
- Neutrophil Extracellular Traps (NETs) are implicated in inflammatory and fibrotic lung diseases.
- The Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) pathway is a key regulator of cellular processes.
Purpose of the Study:
- To elucidate the role of the ERK1/2 signaling pathway in myositis-associated ILD.
- To investigate the contribution of NETs to inflammation and fibrosis in this context.
- To evaluate the therapeutic potential of targeting ERK1/2.
Main Methods:
- Analysis of lung tissues from IIM-ILD patients and experimental autoimmune myositis (EAM) mouse models.
- Assessment of ERK1/2 activation, NETs infiltration, and Epithelial-Mesenchymal Transition (EMT) markers using immunohistochemistry, Western blot, immunofluorescence, and transcriptome sequencing.
- In vivo and in vitro validation using the ERK1/2 inhibitor U0126.
Main Results:
- Activated ERK1/2 and significant NETs infiltration were observed in IIM-ILD and MAILD models.
- NETs induced EMT and pro-inflammatory factor release via ERK1/2 activation.
- Inhibition of NETs formation reduced ERK1/2 phosphorylation and fibrosis.
- U0126 treatment ameliorated NETs-induced EMT, inflammation, and reduced NETs formation in MAILD mice.
Conclusions:
- NETs promote inflammation and fibrosis in myositis-associated ILD by activating the ERK1/2 pathway.
- Targeting ERK1/2 effectively inhibits this pathogenic cascade.
- ERK1/2 inhibition presents a novel therapeutic strategy for myositis-associated ILD.