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Melatonin Alleviates Acute Respiratory Distress Syndrome by Inhibiting Alveolar Macrophage NLRP3 Inflammasomes
Li Zheng1, Wenyu Zhou1, Yutong Wu1
1Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Abstract:
Sepsis-induced acute respiratory distress syndrome (ARDS) is a devastating clinically severe respiratory disorder, and no effective therapy is available. Melatonin (MEL), an endogenous neurohormone, has shown great promise in alleviating sepsis-induced ARDS, but the underlying molecular mechanism remains unclear. Using a lipopolysaccharide (LPS)-treated mouse alveolar macrophage cell line (MH-S) model, we found that MEL significantly inhibited NOD-like receptor protein 3 (NLRP3) inflammasome activation in LPS-treated macrophages, whereas this inhibitory effect of MEL was weakened in MH-S cells transfected with glucose transporter 1 (GLUT1) overexpressing lentivirus. Further experiments showed that MEL downregulated GLUT1 via inhibition of hypoxia-inducible factor 1 (HIF-1α). Notably, hydrogen peroxide (H2O2), a donor of reactive oxygen species (ROS), significantly increased the level of intracellular ROS and inhibited the regulatory effect of MEL on the HIF-1α/GLUT1 pathway. Interestingly, the protective effect of MEL was attenuated after the knockdown of melatonin receptor 1A (MT1) in MH-S cells. We also confirmed in vivo that MEL effectively downregulated the HIF-1α/GLUT1/NLRP3 pathway in the lung tissue of LPS-treated mice, as well as significantly ameliorated LPS-induced lung injury and improved survival in mice. Collectively, these findings revealed that MEL regulates the activation of the ROS/HIF-1α/GLUT1/NLRP3 pathway in alveolar macrophages via the MT1 receptor, further alleviating sepsis-induced ARDS.
Insights
Melatonin (MEL) alleviates sepsis-induced acute respiratory distress syndrome (ARDS) by inhibiting the ROS/HIF-1α/GLUT1/NLRP3 pathway in macrophages via the MT1 receptor. This mechanism improves lung injury and survival in mice.
Area of Science:
- Immunology
- Respiratory Medicine
- Molecular Biology
Background:
- Sepsis-induced acute respiratory distress syndrome (ARDS) is a severe condition with no effective treatments.
- Melatonin (MEL) shows potential for treating sepsis-induced ARDS, but its mechanism is not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanism by which melatonin alleviates sepsis-induced ARDS.
- To investigate the role of the ROS/HIF-1α/GLUT1/NLRP3 pathway in melatonin's protective effects.
Main Methods:
- Utilized a lipopolysaccharide (LPS)-induced mouse alveolar macrophage cell line (MH-S) model.
- Investigated the effects of melatonin on NLRP3 inflammasome activation, glucose transporter 1 (GLUT1) expression, and hypoxia-inducible factor 1 (HIF-1α) levels.
- Examined the role of reactive oxygen species (ROS) and melatonin receptor 1A (MT1) in melatonin's action.
- Validated findings in an in vivo mouse model of LPS-induced lung injury.
Main Results:
- Melatonin inhibited NLRP3 inflammasome activation in LPS-treated macrophages.
- Melatonin downregulated GLUT1 by inhibiting HIF-1α, an effect modulated by ROS.
- Melatonin's protective effect was dependent on the MT1 receptor.
- In vivo, melatonin ameliorated LPS-induced lung injury and improved survival by downregulating the HIF-1α/GLUT1/NLRP3 pathway.
Conclusions:
- Melatonin exerts protective effects against sepsis-induced ARDS by regulating the ROS/HIF-1α/GLUT1/NLRP3 pathway in alveolar macrophages.
- The MT1 receptor mediates melatonin's action in this pathway.
- These findings provide a mechanistic basis for melatonin as a potential therapeutic agent for sepsis-induced ARDS.
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