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MDA5 regulates bleomycin-induced proinflammatory response of macrophages

ABSTRACT: The role of innate immune receptors recognizing RNA and self RNA in lung inflammation and fibrosis formation is not well understood. Here, we demonstrate melanoma differentiation-associated gene 5 (MDA5) regulates bleomycin-induced lung fibrosis, accompanied by increased IL-17+ γδ T cells and neutrophils compared to wild-type (WT) mice. Lung CD11b+ macrophages, with similar characteristics of human Spp1+ macrophages, displayed unique gene expression profiles, marked by elevated levels of ligands for CCR2 and collagen production. Moreover, MDA5 was found to regulate these ligands in bleomycin-treated bone marrow-derived macrophages and U937 cells, contributing to the clearance of extracellular RNA. In conclusion, our findings suggest that MDA5 plays a pivotal role in regulating bleomycin-induced lung fibrosis through influencing the interplay among macrophages, lymphocytes, and neutrophils.

ORGANISM(S): Mus musculus

PROVIDER: GSE272953 | GEO | 2026/07/24

REPOSITORIES: GEO

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Project description:Intratracheal application of bleomycin is known to induce inflammatory and fibrotic reactions in the lung within a short period of time and histological features include infiltration of inflammatory cells, collagen deposition and obliteration of alveolar spaces. Because some of these features are found in patients with idiopathic pulmonary fibrosis (IPF), the bleomycin-induced lung fibrosis animal model is commonly used. However, exploratory treatments that were successfully used in this animal model and progressed to clinical trials lacked significant efficacy in humans. Here, the bleomycin-induced rat lung fibrosis model was studied using whole genome expression data that was collected at various time points and the relevance to human disease was evaluated through comparison with whole genome expression data from IPF patient-derived lung biopsies. The highest gene expression correlation between both species was observed in animals 7 days after bleomycin instillation. These gene expression signatures helped to identify a set of twelve novel disease-relevant translational gene markers that were able to separate IPF patients from controls. Furthermore, three Wnt/-catenin pathway-related genes that belong to this translational gene marker set showed, together with clinical diffusing capacity of the lung for carbon monoxide (DLCO) measurements, the potential to stratify IPF patients according to disease severity. Pirfenidone attenuated a subset of the translational gene markers in the bleomycin-induced fibrosis model, in particular those related to Wnt/-catenin-signaling. This novel translational gene marker panel offers improved possibilities to evaluate disease-modifying efficacy of novel therapeutic concepts in the bleomycin-induced rat lung fibrosis model and could be applied as a diagnostic and prognostic tool for IPF patient care. Comparison of bleomycin-treated and control rats after 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks and 8 weeks; 5 animals per group

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MDA5 regulates bleomycin-induced proinflammatory response of macrophages

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