METTL14-mediated lncRNA NEAT1 promotes asthma progression by regulating the miR-302a-3p/March5 axis

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-05-12 DOI:10.1016/j.intimp.2025.114850

Yawei Wu , Qiuyun Ye , Dandan Chen , Linhui Huang , Rubing Mo , Xingjun Cai

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引用次数: 0

Abstract

Asthma is a chronic inflammatory airway disease with airway remodeling as its main pathological basis. LncRNA NEAT1 has been reported to be up-regulated in asthma, but its upstream and downstream regulatory mechanisms are unclear. This study explored the role and functional mechanism of lncRNA NEAT1 in asthma. Airway smooth muscle cells (ASMCs) isolated from the bronchial tissues of asthmatic patients and healthy volunteers were employed and transfected with an overexpression lentivirus and short hairpin lentivirus. Real-time quantitative PCR (qRT-PCR) and western blotting were used to determine the expression levels of genes. The proliferation and migration of ASMCs were evaluated, and the levels of pro-inflammatory cytokines, inflammasomes, and ROS were determined. Mitophagy was observed by transmission electron microscopy (TEM). An asthma model was established to further confirm the effects of lncRNA NEAT1 on asthma. Our results showed that lncRNA NEAT1 was highly expressed in asthma patient-derived ASMCs. LncRNA NEAT1 enhanced ASMC proliferation and migration, promoted inflammation, and inhibited mitophagy. Treatment with a mitophagy inducer reversed the effects of lncRNA NEAT1. The regulatory axis of lncRNA NEAT1/miR-302a-3p/March5 was confirmed, and lncRNA NEAT1 was found to influence ASMC function via the miR-302a-3p/March5 axis. Moreover, METTL14 was found to enhance lncRNA NEAT1 m6A modification and promote its expression, and thereby participate in the functional regulation of ASMCs. The role of lncRNA NEAT1 was also confirmed in an asthma mouse model, where it alleviated asthma pathology in lncRNA NEAT1 knockdown mice. Collectively, our present study confirmed that METTL14 mediated m6A modification of lncRNA NEAT1 and improved lncRNA NEAT1 expression, which further inhibited mitophagy and promoted asthma progression by regulating the miR-302a-3p/March5 axis. Our study elucidated the mechanism by which lncRNA NEAT1 affects airway remodeling. It also provides valuable insights into the pathogenesis of asthma, and suggests lncRNA NEAT1 as a possible biomarker for asthma.

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mettl14介导的lncRNA NEAT1通过调节miR-302a-3p/March5轴促进哮喘进展

哮喘是一种以气道重塑为主要病理基础的慢性炎症性气道疾病。据报道，LncRNA NEAT1在哮喘中上调，但其上下游调控机制尚不清楚。本研究探讨lncRNA NEAT1在哮喘中的作用及作用机制。采用从哮喘患者和健康志愿者的支气管组织中分离的气道平滑肌细胞（ASMCs），转染过表达慢病毒和短发夹慢病毒。采用实时荧光定量PCR （Real-time quantitative PCR, qRT-PCR）和western blotting检测基因表达水平。评估ASMCs的增殖和迁移，并测定促炎细胞因子、炎性小体和ROS的水平。透射电镜观察线粒体自噬现象。建立哮喘模型，进一步证实lncRNA NEAT1对哮喘的作用。我们的研究结果显示，lncRNA NEAT1在哮喘患者源性asmc中高表达。LncRNA NEAT1增强ASMC增殖和迁移，促进炎症，抑制有丝分裂。用线粒体自噬诱导剂治疗可逆转lncRNA NEAT1的作用。我们确认了lncRNA NEAT1/miR-302a-3p/March5的调控轴，发现lncRNA NEAT1通过miR-302a-3p/March5轴影响ASMC功能。此外，METTL14可增强lncRNA NEAT1 m6A修饰，促进其表达，从而参与ASMCs的功能调控。lncRNA NEAT1的作用也在哮喘小鼠模型中得到证实，它减轻了lncRNA NEAT1敲低小鼠的哮喘病理。综上所述，本研究证实METTL14介导m6A修饰lncRNA NEAT1，改善lncRNA NEAT1表达，通过调节miR-302a-3p/March5轴进一步抑制线粒体自噬，促进哮喘进展。我们的研究阐明了lncRNA NEAT1影响气道重塑的机制。这也为哮喘的发病机制提供了有价值的见解，并提示lncRNA NEAT1可能是哮喘的生物标志物。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.