METTL3-mediated m6A modification of circCDKAL1 regulates macrophage M1 polarization and nasal epithelial cell barrier function in allergic rhinitis through IGF2BP2/JARID2/HMGB1 axis.
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Abstract
Allergic rhinitis (AR) is a chronic inflammatory disease that significantly impairs patients' quality of life, with CircCDKAL1 showing abnormal upregulation in AR patients, though its functional mechanisms remain unclear. In this study, we confirmed the identity of circCDKAL1 and its subcellular localization. Our findings revealed that circCDKAL1 expression was enhanced in samples of AR patients, AR mice and OVA-induced HNEpCs. Besides, circCDKAL1 silencing resulted in improvement of nasal mucosal epithelial barrier function/epithelial cell adhesion and promotion of macrophage M2 polarization in AR. Mechanistically, we discovered that circCDKAL1 was modified by m6A, which was mediated by METTL3. YTHDC1 promoted cytoplasmic output of m6A-modified circCDKAL1. In addition, circCDKAL1 destabilized JARID2 mRNA through interacting with IGF2BP2. Moreover, circCDKAL1 or HMGB1 silencing attenuated JARID2 silencing-mediated damages of epithelial cell adhesion and promotion of macrophage M1 polarization in OVA-induced HNEpCs. In conclusion, METTL3-mediated m6A modification of circCDKAL1, which was transferred from the nucleus to the cytoplasm by YTHDC1, promoted macrophage M1 polarization and impaired nasal mucosal epithelial barrier function/epithelial cell adhesion in AR through interacting with IGF2BP2 and regulating JARID2/HMGB1 axis.
期刊介绍：
Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary.
Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
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