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The impact of m6A methyltransferase METTL3 on airway remodeling in bronchial asthma
Lianqi Peng1,2, Mi Li1,2, Lijun Xiao1,2
1Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Guilin Medical University, Guilin, China.
Background:
Methyltransferase-like 3 (METTL3) is known to play a role in asthma airway remodeling and cell proliferation. Adenylate kinase 4 (AK4) regulates the proliferation of pulmonary artery smooth muscle cells and exerts its effects through the protein kinase B (AKT) pathway. However, the role of METTL3 and AK4-AKT in bronchial smooth muscle cells remains unclear.
Methods:
Systemic METTL3 knockout mice and a mouse model of asthma were established. Airway remodeling was assessed using pulmonary function tests, histopathological staining, and Western blot analysis. RNA sequencing (RNA-seq) was performed to detect changes in gene expression following METTL3 knockdown. The 5-ethynyl-2'-deoxyuridine (EdU) assay was used to evaluate cell proliferation. Finally, the expression levels of relevant proteins were validated by Western blotting.
Results:
Compared with the control model group, the METTL3 knockout group showed significantly reduced inflammatory cell infiltration, decreased collagen fiber deposition, and attenuated airway smooth muscle hyperplasia. RNA-seq revealed that the expression of numerous proliferation-related genes, including AK4, was upregulated following METTL3 knockdown. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that these genes were primarily enriched in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway. The EdU assay demonstrated that METTL3 knockdown inhibited cell proliferation. Western blot validation showed increased AK4 expression in lung tissues of the METTL3 knockout group compared to the control group, while phosphorylated AKT (p-AKT) levels were reduced.
Conclusions:
METTL3 knockout inhibits airway smooth muscle hyperplasia and alleviates airway remodeling in asthma. This effect may be mediated through the regulation of AK4 and the AKT signaling pathway.
Insights
Methyltransferase-like 3 (METTL3) knockout reduces airway remodeling in asthma by inhibiting smooth muscle hyperplasia. This effect is linked to the regulation of Adenylate kinase 4 (AK4) and the AKT signaling pathway.
Area of Science:
- Pulmonary Medicine
- Molecular Biology
- Cell Biology
Background:
- Methyltransferase-like 3 (METTL3) is implicated in asthma airway remodeling and cell proliferation.
- Adenylate kinase 4 (AK4) influences pulmonary artery smooth muscle cell proliferation via the AKT pathway.
- The specific roles of METTL3 and AK4-AKT in bronchial smooth muscle cells are not well-defined.
Purpose of the Study:
- To investigate the role of METTL3 in asthma airway remodeling.
- To explore the involvement of AK4 and the AKT pathway in METTL3-mediated effects on bronchial smooth muscle cells.
Main Methods:
- Utilized systemic METTL3 knockout mice and an asthma mouse model.
- Assessed airway remodeling through pulmonary function tests, histopathology, and Western blotting.
- Employed RNA sequencing (RNA-seq) for gene expression analysis and EdU assays for cell proliferation assessment.
Main Results:
- METTL3 knockout significantly reduced airway inflammation, collagen deposition, and smooth muscle hyperplasia in asthma models.
- RNA-seq identified upregulation of proliferation-related genes, including AK4, upon METTL3 knockdown, enriched in the PI3K/AKT pathway.
- METTL3 knockdown inhibited cell proliferation, with increased AK4 and decreased phosphorylated AKT (p-AKT) observed.
Conclusions:
- METTL3 knockout ameliorates airway remodeling and smooth muscle hyperplasia in asthma.
- The protective effects of METTL3 knockout are potentially mediated by regulating AK4 and the AKT signaling pathway.
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