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Bronchoalveolar Lavage Exosomes in Lipopolysaccharide-induced Septic Lung Injury
Published on: May 21, 2018
Platelet-Derived Exosomal miR-142-3p Inhibits Macrophage M1 Polarization and PANoptosis to Alleviate Acute Lung
Man Zhao1, Quanzhao He1, Ziyuan Wang2
1Department of Critical Care Medicine, Peking University Third Hospital, Beijing100191, China.
Abstract:
Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is an acute, life-threatening form of pulmonary disease characterized by systemic inflammation, for which current treatments are not sufficiently effective. Platelet-derived exosomes (PLT-exos) are noted for their specific targeting ability to inflammatory sites, minimal immunogenicity, and positive anti-inflammatory effects, positioning them as a promising therapeutic candidate. However, the specific effects and mechanisms of PLT-exos in ALI/ARDS remain poorly understood. Here, utilizing a lipopolysaccharide (LPS)-induced ALI model in murine and cell models, we first demonstrated that activated platelet-derived exosomes (AP-exos) are preferentially taken up by lung macrophages, leading to suppressed macrophage M1 polarization and PANoptosis and reduced lung inflammation and injury, which were closely linked to the inhibition of MAPK pathway activity. Mechanistically, the protective effects of AP-exos were partially mediated by the highly enriched miR-142-3p, as evidenced by the intervention with miR-142-3p significantly inhibiting their protective effect against LPS-induced ALI injury in mice. Furthermore, we noted a negative correlation between the level of miR-142-3p derived from plasma exosomes and the severity of ARDS, suggesting its potential in predicting the severity of ARDS. Further investigation revealed that TMEM120B (T120B) functions as a downstream target of miR-142-3p. Overall, the findings suggested that activated platelets release exosomes that inhibit macrophage M1 polarization and PANoptosis, contributing to the pathogenesis of ARDS via the miR-142-3p/T120B/MAPK axis.
Insights
Activated platelet-derived exosomes (AP-exos) reduce lung inflammation and injury in acute lung injury by suppressing macrophage M1 polarization and PANoptosis via the miR-142-3p/T120B/MAPK pathway.
Area of Science:
- Pulmonary Medicine
- Immunology
- Cell Biology
Background:
- Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a severe inflammatory lung condition with limited treatment options.
- Platelet-derived exosomes (PLT-exos) show potential therapeutic benefits due to their anti-inflammatory properties and targeting capabilities.
- The precise mechanisms of PLT-exos in ALI/ARDS pathogenesis are not fully understood.
Purpose of the Study:
- To investigate the therapeutic effects and underlying mechanisms of activated platelet-derived exosomes (AP-exos) in a lipopolysaccharide (LPS)-induced ALI model.
- To explore the role of miR-142-3p and its downstream targets in AP-exos-mediated protection against ALI/ARDS.
Main Methods:
- Established a lipopolysaccharide (LPS)-induced ALI model in murine and cell cultures.
- Investigated the uptake of AP-exos by lung macrophages and their effects on M1 polarization and PANoptosis.
- Analyzed the involvement of the MAPK pathway, miR-142-3p, and TMEM120B (T120B) in the therapeutic mechanism.
Main Results:
- AP-exos were preferentially taken up by lung macrophages, suppressing M1 polarization and PANoptosis, thereby reducing lung inflammation and injury.
- The protective effects were linked to the inhibition of the MAPK pathway.
- miR-142-3p, enriched in AP-exos, partially mediated the protective effects, and its plasma levels correlated negatively with ARDS severity. TMEM120B was identified as a downstream target of miR-142-3p.
Conclusions:
- Activated platelet-derived exosomes exert protective effects against ALI/ARDS by inhibiting macrophage M1 polarization and PANoptosis.
- The miR-142-3p/T120B/MAPK axis is a key mechanism underlying the therapeutic action of AP-exos in ALI/ARDS.
- Plasma exosomal miR-142-3p may serve as a potential biomarker for predicting ARDS severity.