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Published on: September 18, 2020
MBD2 serves as a viable target against pulmonary fibrosis by inhibiting macrophage M2 program
Yi Wang1, Lei Zhang1, Guo-Rao Wu1
1The Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, 1095 Jiefang Ave., Wuhan 430030, China.
Abstract:
Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. Here, we demonstrated that lungs originating from different types of patients with PF, including coronavirus disease 2019, systemic sclerosis-associated interstitial lung disease, and idiopathic PF, and from mice following bleomycin (BLM)-induced PF are characterized by the altered methyl-CpG-binding domain 2 (MBD2) expression in macrophages. Depletion of Mbd2 in macrophages protected mice against BLM-induced PF. Mbd2 deficiency significantly attenuated transforming growth factor-β1 (TGF-β1) production and reduced M2 macrophage accumulation in the lung following BLM induction. Mechanistically, Mbd2 selectively bound to the Ship promoter in macrophages, by which it repressed Ship expression and enhanced PI3K/Akt signaling to promote the macrophage M2 program. Therefore, intratracheal administration of liposomes loaded with Mbd2 siRNA protected mice from BLM-induced lung injuries and fibrosis. Together, our data support the possibility that MBD2 could be a viable target against PF in clinical settings.
Insights
Methyl-CpG-binding domain 2 (MBD2) in macrophages drives pulmonary fibrosis (PF). Inhibiting MBD2 in macrophages protects against PF by reducing inflammation and fibrosis, suggesting MBD2 as a therapeutic target.
Area of Science:
- Immunology
- Molecular Biology
- Pulmonary Medicine
Background:
- Pulmonary fibrosis (PF) mechanisms remain unclear despite extensive research.
- Altered methyl-CpG-binding domain 2 (MBD2) expression in macrophages is observed in various PF types.
Purpose of the Study:
- To investigate the role of MBD2 in macrophage function during pulmonary fibrosis.
- To explore MBD2 as a potential therapeutic target for PF.
Main Methods:
- Studied MBD2 expression in macrophages from PF patients and BLM-induced mouse models.
- Utilized Mbd2-deficient macrophages and Mbd2 siRNA in mouse models of PF.
- Analyzed transforming growth factor-β1 (TGF-β1) production and M2 macrophage accumulation.
- Investigated MBD2 binding to the Ship promoter and its effect on PI3K/Akt signaling.
Main Results:
- MBD2 expression was altered in macrophages across different PF types and in BLM-induced PF.
- Macrophage Mbd2 depletion protected mice from BLM-induced PF.
- Mbd2 deficiency reduced TGF-β1 production and M2 macrophage accumulation.
- MBD2 represses Ship expression, enhancing PI3K/Akt signaling and promoting M2 macrophage polarization.
- Intratracheal Mbd2 siRNA delivery ameliorated BLM-induced lung injury and fibrosis.
Conclusions:
- MBD2 plays a critical role in macrophage-mediated pulmonary fibrosis.
- Targeting MBD2, particularly in macrophages, presents a promising therapeutic strategy for PF.
- MBD2 inhibition offers a potential clinical approach to treat lung fibrosis.
