Local administration of liposomal-based Plekhf1 gene therapy attenuates pulmonary fibrosis by modulating macrophage
Lifeng Yan1, Chenchen Hou1, Juan Liu1
1Department of Respiratory and Critical Care Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
Abstract:
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Macrophages, particularly alternatively activated macrophages (M2), have been recognized to contribute to the pathogenesis of pulmonary fibrosis. Therefore, targeting macrophages might be a viable therapeutic strategy for IPF. Herein, we report a potential nanomedicine-based gene therapy for IPF by modulating macrophage M2 activation. In this study, we illustrated that the levels of pleckstrin homology and FYVE domain containing 1 (Plekhf1) were increased in the lungs originating from IPF patients and PF mice. Further functionality studies identified the pivotal role of Plekhf1 in macrophage M2 activation. Mechanistically, Plekhf1 was upregulated by IL-4/IL-13 stimulation, after which Plekhf1 enhanced PI3K/Akt signaling to promote the macrophage M2 program and exacerbate pulmonary fibrosis. Therefore, intratracheal administration of Plekhf1 siRNA-loaded liposomes could effectively suppress the expression of Plekhf1 in the lungs and notably protect mice against BLM-induced lung injury and fibrosis, concomitant with a significant reduction in M2 macrophage accumulation in the lungs. In conclusion, Plekhf1 may play a crucial role in the pathogenesis of pulmonary fibrosis, and Plekhf1 siRNA-loaded liposomes might be a promising therapeutic approach against pulmonary fibrosis.
Insights
Targeting Pleckstrin homology and FYVE domain containing 1 (Plekhf1) may treat idiopathic pulmonary fibrosis (IPF). Suppressing Plekhf1 with siRNA liposomes reduced lung fibrosis and M2 macrophage activation in mice.
Area of Science:
- Pulmonary Medicine
- Immunology
- Nanomedicine
Background:
- Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with few treatments.
- Macrophages, especially M2 types, are implicated in fibrosis development.
- Targeting macrophages presents a potential therapeutic avenue for IPF.
Purpose of the Study:
- To investigate the role of Pleckstrin homology and FYVE domain containing 1 (Plekhf1) in macrophage M2 activation and IPF pathogenesis.
- To evaluate the therapeutic potential of Plekhf1 siRNA-loaded liposomes for IPF treatment.
Main Methods:
- Quantified Plekhf1 levels in IPF patient and mouse lungs.
- Investigated Plekhf1's function in M2 macrophage activation.
- Administered Plekhf1 siRNA-loaded liposomes intratracheally to mice with bleomycin-induced lung injury.
Main Results:
- Plekhf1 levels were elevated in IPF lungs and mice.
- Plekhf1 upregulation by IL-4/IL-13 enhanced PI3K/Akt signaling, promoting M2 activation and fibrosis.
- Liposomal Plekhf1 siRNA suppressed Plekhf1 expression, reduced M2 macrophages, and protected against lung injury and fibrosis.
Conclusions:
- Plekhf1 plays a critical role in the pathogenesis of pulmonary fibrosis.
- Plekhf1 siRNA-loaded liposomes show promise as a therapeutic strategy for IPF.
