Journal
HUMAN MOLECULAR GENETICS
Volume 31, Issue 4, Pages 638-650Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddab283
Keywords
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Funding
- National Natural Science Foundation of China [U2004127]
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Activated neutrophil-derived CRNDE is transferred to ASMCs through exosomes, activating the NF-kappa B pathway and promoting the proliferation and migration of ASMCs, which contributes to airway remodeling in asthma.
Activated neutrophil-derived exosomes reportedly contribute to the proliferation of airway smooth muscle cells (ASMCs), thereby aggravating the airway wall remodeling during asthma; however, the specific mechanism remains unclear. Lipopolysaccharide (LPS)-EXO and si-CRNDE-EXO were extracted from the media of human neutrophils treated with LPS and LPS + si-CRNDE (a siRNA targets long non-coding RNA CRNDE), respectively. Human ASMCs were co-cultured with LPS-EXO or si-CRNDE-EXO, and cell viability, proliferation and migration were measured. The interplay of colorectal neoplasia differentially expressed (CRNDE), inhibitor of nuclear factor kappa B kinase subunit beta (IKK beta) and nuclear receptor subfamily 2 group C member 2 (TAK1) was explored using RNA immunoprecipitation (RIP) and Co-IP assays. A mouse model of asthma was induced using ovalbumin. CRNDE was upregulated in LPS-EXO and successfully transferred from LPS-treated neutrophils to ASMCs through exosome. Mechanically, CRNDE loaded in LPS-EXO reinforced TAK1-mediated IKK beta phosphorylation, thereby activating the nuclear factor kappa B (NF-kappa B) pathway. Functionally, silencing CRNDE in LPS-EXO, an IKK beta inhibitor, and an NF-kappa B inhibitor all removed the upregulation of cell viability, proliferation and migration induced by LPS-EXO in ASMCs. In the end, the in vivo experiment demonstrated that CRNDE knockdown in neutrophils effectively reduced the thickness of bronchial smooth muscle in a mouse model for asthma. Activated neutrophils-derived CRNDE was transferred to ASMCs through exosomes and activated the NF-kappa B pathway by enhancing IKK beta phosphorylation. The latter promoted the proliferation and migration of ASMCs and then contributed to airway remodeling in asthma.
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