Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) is characterized by persistent mucosal inflammation and tissue remodeling, driven by the crosstalk between epithelial and immune cells. Emerging evidence indicates that, in addition to IL-13, TSLP, and IL-33, other mediators also significantly contribute to the crosstalk. In this study, we investigate the mechanism by which epithelial cell mitochondrial dysfunction drives immune dysregulation in CRSwNP, aiming to uncover novel therapeutic targets. We analyzed transcriptomic data from three GEO datasets (GSE194282, GSE72713, GSE36830) to identify Differentially Expressed Genes (DEGs). By integrating mitochondrial-associated genes (MitoCarta3.0), we performed functional enrichment (GO/KEGG) and PPI network analyses to identify hub genes. In vitro experiments, including western blotting, flow cytometry, and immunofluorescence, were applied to elucidated the role of COX5A in mediating M2 macrophage polarization via ROS production. A murine nasal polyp (NP) model further confirmed key findings. We identified 110 mitochondrial-related DEGs (80 upregulated, 30 downregulated), prominently enriched in immune regulation and mitochondrial respiratory chain. Immune infiltration analysis revealed significant upregulation of M2 macrophages and resting memory CD4+T cells in CRSwNP tissues. Strikingly, IL-13-stimulated epithelial cells (ECs) drove M2 polarization via COX5A-mediated ROS production—an effect abolished by COX5A knockdown or ROS scavengers. Furthermore, a murine nasal polyps model confirmed elevated COX5A and M2 marker expression, reinforcing the clinical relevance of our findings. Our research highlights the crucial role of mitochondrial dysfunction, particularly through COX5A-mediated reactive oxygen species (ROS) generation, in promoting the polarization of M2 macrophages and the progression of CRSwNP. These findings emphasize the potential for targeting mitochondrial-immune crosstalk as an effective therapeutic strategy, thereby opening new avenues for addressing CRSwNP.
Wang et al. (Tue,) studied this question.