1. Long non-coding RNA NEAT1 exacerbates NLRP3-mediated pyroptosis in allergic rhinitis through regulating the PTBP1/FOXP1 cascade.
- Author
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Liu Y, Gao J, Xu Q, Wang X, Zhong W, Wu F, Lin X, Zhang Q, and Ye Q
- Subjects
- Animals, Humans, Mice, Mice, Inbred BALB C, Ovalbumin immunology, Heterogeneous-Nuclear Ribonucleoproteins metabolism, Heterogeneous-Nuclear Ribonucleoproteins genetics, Signal Transduction, Disease Models, Animal, Female, Cytokines metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, NLR Family, Pyrin Domain-Containing 3 Protein genetics, RNA, Long Noncoding genetics, RNA, Long Noncoding metabolism, Pyroptosis, Rhinitis, Allergic immunology, Rhinitis, Allergic pathology, Rhinitis, Allergic genetics, Rhinitis, Allergic metabolism, Forkhead Transcription Factors metabolism, Forkhead Transcription Factors genetics, Nasal Mucosa immunology, Nasal Mucosa pathology, Nasal Mucosa metabolism
- Abstract
Background: Allergic Rhinitis (AR) is a prevalent chronic non-infectious inflammation affecting the nasal mucosa. NLRP3-mediated pyroptosis of epithelial cells plays a pivotal role in AR pathogenesis. Herein, we evaluated the impact of the long non-coding RNA nuclear paraspeckle assembly transcript 1 (lncRNA NEAT1) on NLR family pyrin domain containing 3 (NLRP3)-mediated pyroptosis in AR., Methods: Nasal inflammation levels in ovalbumin (OVA)-induced AR mice were assessed using HE staining, and NLRP3 expression was evaluated through immunohistochemistry. ELISA was utilized to detect OVA-specific IgE, IL-6, IL-5, and inflammatory cytokines (IL-1β, IL-18). Human nasal epithelial cells (HNEpCs) stimulated with IL4/IL13 were used to analyze the mRNA and protein levels of associated genes utilizing RT-qPCR and western blot, respectively. Cell viability and pyroptosis were assessed by CCK-8 and flow cytometry. The targeting relationship between NEAT1, PTBP1 and FOXP1 were analyzed by RIP and RNA pull down assays. FISH and IF analysis were performed to assess the co-localization of NEAT1 and PTBP1., Results: In both the AR mouse and cellular models, increased levels of NEAT1, PTBP1 and FOXP1 were observed. AR mice exhibited elevated inflammatory infiltration and pyroptosis, evidenced by enhanced expressions of OVA-specific IgE, IL-6, and IL-5, NLRP3, Cleaved-caspase 1, GSDMD-N, IL-1β and IL-18. Functional assays revealed that knockdown of PTBP1 or NEAT1 inhibited pyroptosis while promoting the proliferation of IL4/IL13-treated HNEpCs. Mechanistically, NEAT1 directly interacted with PTBP1, thereby maintaining FOXP1 mRNA stability. Rescue assays demonstrated that FOXP1 upregulation reversed the inhibitory effects of silencing NEAT1 or PTBP1 on IL4/IL13-stimulated pyroptosis activation in HNEpCs., Conclusion: NEAT1 acts as a RNA scaffold for PTBP1, activating the PTBP1/FOXP1 signaling cascade, subsequently triggering NLRP3-mediated pyroptosis in HNEpCs, and ultimately promoting AR progression. These findings highlight some new insights into the pathogenesis of AR., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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