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RNA m⁶A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis.

ABSTRACT: N⁶-methyladenosine (m⁶A), the most prevalent mRNA modification, has an important function in diverse biological processes. However, the involvement of m⁶A in allergic asthma and macrophage homeostasis remains largely unknown. Here we show that m⁶A methyltransferases METTL3 is expressed at a low level in monocyte-derived macrophages from childhood allergic asthma patients. Conditional knockout of Mettl3 in myeloid cells enhances Th2 cell response and aggravates allergic airway inflammation by facilitating M2 macrophage activation. Loss and gain functional studies confirm that METTL3 suppresses M2 macrophage activation partly through PI3K/AKT and JAK/STAT6 signaling. Mechanistically, m⁶A-sequencing shows that loss of METTL3 impairs the m⁶A-YTHDF3-dependent degradation of PTX3 mRNA, while higher PTX3 expression positively correlates with asthma severity through promoting M2 macrophage activation. Furthermore, the METTL3/YTHDF3-m⁶A/PTX3 interactions contribute to autophagy maturation in macrophages by modulating STX17 expression. Collectively, this study highlights the function of m⁶A in regulating macrophage homeostasis and identifies potential targets in controlling allergic asthma.

SUBMITTER: Han X

PROVIDER: S-EPMC10643624 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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RNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis.

Han Xiao X Liu Lijuan L Huang Saihua S Xiao Wenfeng W Gao Yajing Y Zhou Weitao W Zhang Caiyan C Zheng Hongmei H Yang Lan L Xie Xueru X Liang Qiuyan Q Tu Zikun Z Yu Hongmiao H Fu Jinrong J Wang Libo L Zhang Xiaobo X Qian Liling L Zhou Yufeng Y

Nature communications 20231113 1

N6-methyladenosine (m6A), the most prevalent mRNA modification, has an important function in diverse biological processes. However, the involvement of m6A in allergic asthma and macrophage homeostasis remains largely unknown. Here we show that m6A methyltransferases METTL3 is expressed at a low level in monocyte-derived macrophages from childhood allergic asthma patients. Conditional knockout of Mettl3 in myeloid cells enhances Th2 cell response and ag ...[more]

PMID: 37957139

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Project description:BackgroundAngiotensin (Ang)-(1-7) can reduce airway inflammation and airway remodeling in allergic asthma. Autophagy-related 5 (ATG5) has attracted wide attentions in asthma. However, the effects of Ang-(1-7) on ATG5-mediated autophagy in allergic asthma are unclear.MethodsIn this study, human bronchial epithelial cell (BEAS-2B) and human bronchial smooth muscle cell (HBSMC) were treated with different dose of Ang-(1-7) to observe changes of cell viability. Changes of ATG5 protein expression were measured in 10 ng/mL of interleukin (IL)-13-treated cells. Transfection of ATG5 small interference RNA (siRNA) or ATG5 cDNA in cells was used to analyze the effects of ATG5 on secretion of cytokines in the IL-13-treated cells. The effects of Ang-(1-7) were compared to the effects of ATG5 siRNA transfection or ATG5 cDNA transfection in the IL-13-treated cells. In wild-type (WT) mice and ATG5 knockout (ATG5-/-) mice, ovalbumin (OVA)-induced airway inflammation, fibrosis and autophagy were observed. In the OVA-induced WT mice, Ang-(1-7) treatment was performed to observe its effects on airway inflammation, fibrosis and autophagy.ResultsThe results showed that ATG5 protein level was decreased with Ang-(1-7) dose administration in the IL-13-treated BEAS-2B and IL13-treated HBSMC. Ang-(1-7) played similar results to ATG5 siRNA that it suppressed the secretion of IL-25 and IL-13 in the IL-13-treated BEAS-2B cells, and inhibited the expression of transforming growth factor (TGF)-β1 and α-smooth muscle actin (α-SMA) protein in the IL-13-treated HBSMC cells. ATG5 cDNA treatment significantly increased the secretion of IL-25 and IL-13 and expression of TGF-β1 and α-SMA protein in IL-13-treated cells. Ang-(1-7) treatment suppressed the effects of ATG5 cDNA in the IL-13-treated cells. In OVA-induced WT mice, Ang-(1-7) treatment suppressed airway inflammation, remodeling and autophagy. ATG5 knockout also suppressed the airway inflammation, remodeling and autophagy.ConclusionsAng-(1-7) treatment suppressed airway inflammation and remodeling in allergic asthma through inhibiting ATG5, providing an underlying mechanism of Ang-(1-7) for allergic asthma treatment.

Dataset Information

RNA m⁶A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis.

Publications

RNA m<sup>6</sup>A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis.

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