MBD2 serves as a viable target against pulmonary fibrosis by inhibiting macrophage M2 program

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.

A cohort autopsy study defines COVID-19 systemic pathogenesis

“… 2 , 30 In addition, a subset of macrophages harboring tissue repair and fibrosis generation signature has been reported in severe COVID-19 patients, extending the potential pathogenicity of infiltrating macrophages to fibrosis. 56 , 57 Therefore, circulating monocytes and tissue infiltrating macrophages are pivotal for systemic and local immune disorders, viral infection, and tissue injuries. Comprehensive evaluations of the signatures of monocytes and macrophages via multimodal single-cell profiling may promote our understanding of the molecular features, activation status, spatial and chronological distribution of monocytes and macrophages in the unique inflammatory milieu of COVID-19, thus benefiting targeted therapeutics.…”

Is the Macrophage Phenotype Determinant for Fibrosis Development?

“…( Level of fibrosis (hydroxyproline), expression of fibrotic markers (collagen, α-SMA), and M2 marker (Arg1) were reduced by the treatment with siRNA of MBD2. [69] The sphingosine-1-phosphate receptor-2 (S1PR2) is being extensively studied due to its association with pulmonary fibrosis and its pro-fibrotic role. It is expressed in alveolar macrophages, vascular endothelial cells, and alveolar epithelial cells.…”

Targeted Inhibition of FTO Demethylase Protects Mice Against LPS-Induced Septic Shock by Suppressing NLRP3 Inflammasome

“…Preparation and Characterization of siRNA-Loaded Liposomes siRNA-loaded liposomes were prepared as described previously (29,30). Briefly, lipoid, cholesterol, DSPC, and mPEG-DMG were dissolved in ethanol at a specific molar ratio.…”