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Respiratory Research

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Open Access 01-12-2022 | Idiopathic Pulmonary Fibrosis | Research

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

Authors: Wanhai Qin, C. Arnold Spek, Brendon P. Scicluna, Tom van der Poll, JanWillem Duitman

Published in: Respiratory Research | Issue 1/2022

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.

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Title: Myeloid DNA methyltransferase3b deficiency aggravates pulmonary fibrosis by enhancing profibrotic macrophage activation
Authors: Wanhai Qin
C. Arnold Spek
Brendon P. Scicluna
Tom van der Poll
JanWillem Duitman
Publication date: 01-12-2022
Publisher: BioMed Central
Keyword: Idiopathic Pulmonary Fibrosis
Published in: Respiratory Research / Issue 1/2022
Electronic ISSN: 1465-993X
DOI: https://doi.org/10.1186/s12931-022-02088-5

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