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IL-33-ST2 pathway regulates AECII transdifferentiation by targeting alveolar macrophage in a bronchopulmonary
Yue Zhu1, Hui-Ci Yao1, Hong-Yan Lu1
1Department of Pediatrics, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.
Abstract:
Evidence points to the indispensable function of alveolar macrophages (AMs) in normal lung development and tissue homeostasis. However, the importance of AMs in bronchopulmonary dysplasia (BPD) has not been elucidated. Here, we identified a significant role of abnormal AM proliferation and polarization in alveolar dysplasia during BPD, which is closely related to the activation of the IL-33-ST2 pathway. Compared with the control BPD group, AMs depletion partially abolished the epithelialmesenchymal transition process of AECII and alleviated pulmonary differentiation arrest. In addition, IL-33 or ST2 knockdown has protective effects against lung injury after hyperoxia, which is associated with reduced AM polarization and proliferation. The protective effect disappeared following reconstitution of AMs in injured IL-33 knockdown mice, and the differentiation of lung epithelium was blocked again. In conclusion, the IL-33-ST2 pathway regulates AECII transdifferentiation by targeting AMs proliferation and polarization in BPD, which shows a novel strategy for manipulating the IL-33-ST2-AMs axis for the diagnosis and intervention of BPD.
Insights
Alveolar macrophages (AMs) drive bronchopulmonary dysplasia (BPD) by activating the IL-33-ST2 pathway. Targeting this pathway offers a new strategy for BPD diagnosis and treatment.
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Immunology
Background:
- Alveolar macrophages (AMs) are crucial for lung development and homeostasis.
- The role of AMs in bronchopulmonary dysplasia (BPD) remains unclear.
Purpose of the Study:
- To investigate the role of AMs and the IL-33-ST2 pathway in BPD pathogenesis.
- To explore potential therapeutic strategies targeting the IL-33-ST2-AMs axis in BPD.
Main Methods:
- Utilized a mouse model of BPD induced by hyperoxia.
- Investigated AM proliferation and polarization.
- Assessed epithelial-mesenchymal transition of alveolar epithelial cells type II (AECII).
- Manipulated IL-33 and ST2 expression via knockdown and AM reconstitution.
Main Results:
- Abnormal AM proliferation and polarization were observed in BPD, linked to IL-33-ST2 pathway activation.
- AM depletion alleviated epithelial-mesenchymal transition and pulmonary differentiation arrest in BPD.
- IL-33 or ST2 knockdown protected against hyperoxia-induced lung injury by reducing AMs polarization and proliferation.
- Reconstitution of AMs in IL-33 knockdown mice reversed the protective effects and blocked lung epithelium differentiation.
Conclusions:
- The IL-33-ST2 pathway regulates AECII transdifferentiation by targeting AMs proliferation and polarization in BPD.
- The IL-33-ST2-AMs axis represents a novel therapeutic target for BPD diagnosis and intervention.
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