Myeloid DNA methyltransferase3b deficiency aggravates pulmonary fibrosis by enhancing profibrotic macrophage activation

Abstract

Background Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and severe disease characterized by excessive matrix deposition in the lungs. Macrophages play crucial roles in maintaining lung homeostasis but are also central in the pathogenesis of lung diseases like pulmonary fibrosis. Especially, macrophage polarization/activation seems to play a crucial role in pathology and epigenetic reprograming is well-known to regulate macrophage polarization. DNA methylation alterations in IPF lungs have been well documented, but the role of DNA methylation in specific cell types, especially macrophages, is poorly defined. Methods In order to determine the role of DNA methylation in macrophages during pulmonary fibrosis, we subjected macrophage specific DNA methyltransferase (DNMT)3B, which mediates the de novo DNA methylation, deficient mice to the bleomycin-induced pulmonary fibrosis model. Macrophage polarization and fibrotic parameters were evaluated at 21 days after bleomycin administration. Dnmt3b knockout and wild type bone marrow-derived macrophages were stimulated with either interleukin (IL)4 or transforming growth factor beta 1 (TGFB1) in vitro, after which profibrotic gene expression and DNA methylation at the Arg1 promotor were determined. Results We show that DNMT3B deficiency promotes alternative macrophage polarization induced by IL4 and TGFB1 in vitro and also enhances profibrotic macrophage polarization in the alveolar space during pulmonary fibrosis in vivo. Moreover, myeloid specific deletion of DNMT3B promoted the development of experimental pulmonary fibrosis. Conclusions In summary, these data suggest that myeloid DNMT3B represses fibrotic macrophage polarization and protects against bleomycin induced pulmonary fibrosis.

Macrophage Implication in IPF: Updates on Immune, Epigenetic, and Metabolic Pathways

“…This was associated with an increased expression of M2 genes such as Arg1, Fizz1, Pdgfa, and Mmp8. Consistently, DNMT3B deficiency in myeloid cells exacerbates pulmonary fibrosis, suggesting a protective role for DNMT3B in IPF via the regulation of macrophage polarization [109].…”

DNA methylation modification in Idiopathic pulmonary fibrosis

“…DNMT3b is a major DNMT in de novo DNA methylation, which regulates macrophage polarization ( Yang et al, 2014 ). DNMT3b deficiency can promote IL4-and TGF-β1-induced replacement macrophage polarization in vitro , and enhance the pro-fibrotic macrophage polarization in the alveolar space during pulmonary fibrosis in vivo , thus promoting the pulmonary fibrosis process ( Qin et al, 2022 ). Recently, the increased DNMT1/DNMT3a were also found in IPF patients and Blm-treated mice lungs ( Wei et al, 2022 ).…”

Epigenetics Approaches toward Precision Medicine for Idiopathic Pulmonary Fibrosis: Focus on DNA Methylation

“…On the contrary, another study provided different results. Qin et al found that DNMT3b ameliorates the development of bleomycin-induced pulmonary fibrosis by limiting M2 macrophage polarization [ 123 ]. In this case, DNMT3b acts as a negative regulator of M2 macrophage polarization.…”