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IRF4 Knockdown Inhibits the Chronic Rhinosinusitis Without Nasal Polyps Development by Regulating
Jun Xu1, Jiahui Li2, Xiaoya Wang2
1Department of Otorhinolaryngology, Guangzhou Women and Children's Medical Center, National Children's Medical Center for South Central Region, Guangzhou Medical University, Guangzhou, No. 9, Jinsui Road, Guangzhou, 510623, China. ent_xujun@gzhmu.edu.cn.
Abstract:
Chronic rhinosinusitis without nasal polyps (CRSsNP) is a CRS phenotype. However, the mechanisms of CRSsNP remains unclear. Differentially expressed genes (DEGs) were obtained from the GSE36830 and GSE198950 datasets through the GEO2R tool. The six hub genes were screened by the protein-protein interaction (PPI) network analysis and Cytoscape software. Then we constructed the mouse models of CRS and verified the expression levels of hub genes by reverse transcription quantitative PCR (RT-qPCR). Hematoxylin-eosin (HE) staining was employed to observe pathological alterations in mouse tissues. Casepase-3 expression was detected by immunohistochemistry (IHC). The levels of TNF-α, IL-12, IL-6, IL-1β, LDH, and IL-18 were evaluated using enzyme-linked immunosorbent assay (ELISA). Pyroptosis-related protein expressions were measured by western blotting. Cell counting kit-8 (CCK-8) and flow cytometry were performed to assess the proliferation and apoptosis of lipopolysaccharide (LPS)-induced NP69 cells. Six hub DEGs were identified. The expression levels of IRF4, IKZF1, and CD79A were obviously increased in CRSsNP, while those of ADH6, ADH1A, and LDHC were significantly decreased. IRF4 knockdown attenuated the pathologic features of CRSsNP. IRF4 knockdown reduced levels of the TNF-α, IL-12, IL-6 IL-1β, LDH, and IL-18 as well as the proteins expression of Casepase-1, GSDMD, and NLRP3 both in vivo and in vitro, implying that inflammation and pyroptosis were inhibited. IRF4 knockdown hinders the development of CRSsNP by inhibiting the inflammatory response and NLRP3/Caspase-1/GSDMD-mediated pyroptosis, which offers novel promising treatment strategies for clinical intervention.
Insights
Investigating chronic rhinosinusitis without nasal polyps (CRSsNP), this study identified IRF4 as a key gene. Reducing IRF4 levels inhibited inflammation and pyroptosis, offering potential new treatments for CRSsNP.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Chronic rhinosinusitis without nasal polyps (CRSsNP) is a common phenotype of chronic rhinosinusitis (CRS), but its underlying mechanisms remain poorly understood.
- Identifying key molecular players in CRSsNP pathogenesis is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To elucidate the molecular mechanisms of CRSsNP by identifying differentially expressed genes (DEGs) and hub genes.
- To investigate the role of identified hub genes, particularly IRF4, in CRSsNP pathogenesis and explore its potential as a therapeutic target.
Main Methods:
- Differential gene expression analysis of CRSsNP datasets (GSE36830, GSE198950) using GEO2R.
- Protein-protein interaction network analysis and Cytoscape to screen for six hub genes.
- Construction of mouse models for CRSsNP and validation of gene expression via RT-qPCR, HE staining, and IHC.
- Measurement of inflammatory cytokines (TNF-α, IL-12, IL-6, IL-1β, IL-18) and LDH using ELISA.
- Western blotting for pyroptosis-related proteins (NLRP3, Caspase-1, GSDMD).
- In vitro studies using LPS-induced NP69 cells to assess proliferation (CCK-8) and apoptosis (flow cytometry).
Main Results:
- Six hub differentially expressed genes (DEGs) were identified in CRSsNP.
- IRF4, IKZF1, and CD79A showed increased expression, while ADH6, ADH1A, and LDHC were decreased in CRSsNP.
- Knockdown of IRF4 significantly attenuated CRSsNP pathological features in mouse models.
- IRF4 knockdown reduced inflammatory cytokine levels and inhibited NLRP3/Caspase-1/GSDMD-mediated pyroptosis both in vivo and in vitro.
Conclusions:
- IRF4 plays a critical role in the pathogenesis of CRSsNP by promoting inflammation and pyroptosis.
- IRF4 knockdown effectively inhibits the inflammatory response and pyroptosis, suggesting it as a promising therapeutic target for CRSsNP.
- This study provides novel insights into CRSsNP mechanisms and potential clinical intervention strategies.
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