Role of tissue remodeling and reduced antimicrobial activity in recurrent chronic rhinosinusitis with nasal polyps

The pathophysiological mechanisms of recurrent chronic rhinosinusitis with nasal polyps (CRSwNP) remains incompletely understood. Next-generation sequencing coupled with bioinformatic analysis allows to characterize the global transcriptomic profile, identify key mechanisms, pathways, and potential novel drug targets. Methods: Whole-transcriptome sequencing was performed on 16 nasal polyps (CRSwNP-NP) and paired nasal mucosa (CRSwNP-NM) samples from patients with recurrent CRSwNP and on 15 nasal mucosa samples from non-CRS controls (CS-NM). Differentially expressed genes (DEGs) were determined and enrichment analyses were performed using the Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Reactome databases. Results: CRSwNP-NP tissues were differentiated from CS-NM by 183 DEGs and from CRSwNP-NM by 293 DEGs. When comparing nasal mucosa from CRS and non-CRS patients192 DEGs were identified. Enrichment analysis of nasal polyp tissues revealed that the most significantly upregulated gene sets were involved in positive regulation of extracellular signal-regulated kinase 1/2 cascade, hypoxia-inducible factor-1 pathway and overactivation of renin-angiotensin-aldosterone system. Conversely, the downregulated gene sets were predominantly associated with impaired antimicrobial functions. Comparing CRS and non-CRS patients' nasal mucosa, glycan metabolism was significantly upregulated, while retinol metabolism was downregulated. Conclusion: The main pathways in the polyps are associated with tissue remodeling, increased renin-angiotensin-aldosterone system activation, decreased antimicrobial defense as local microenvironmental risk factors contributing to the recurrence of CRSwNP. Impaired retinol metabolism, which may promote fibrin deposition, could represent a systemic susceptibility factor. These findings open perspectives for novel therapeutic interventions.