A Co-expression Network Identifies a Dominant Immune-Activation Module Predicting Severity in Nasal Polyps 2310328

Abstract Introduction Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disease of the upper airway, yet the molecular pathways underpinning nasal polyps (NP) immunopathogenesis and endotypic diversity remain incompletely understood. Methods We profiled tissue bulk RNA-seq from 88 NP and 317 ethmoids from CRS. Weighted gene co‑expression network analysis (WGCNA) identified NP-associated modules, followed by differential expression and functional enrichment. Results WGCNA revealed six NP-associated modules compared to ethmoids, and the blue module was most NP-associated. Blue-module pathways were enriched for cytokine/chemokine receptor signaling, hematopoietic regulation, and immune differentiation, consistent with type 2 and mixed inflammatory programs. GSEA further highlighted cell adhesion/activation, leukocyte and mononuclear cell migration, actin filament organization, and GPCR signaling, supporting coordinated immune trafficking and epithelial—immune crosstalk in NP progression. Blue-module PPI mapping converged on SYK/BTK-centered B cell/Fc receptor signaling, integrin—ICAM1 adhesion/migration, and epithelial cytoskeletal remodeling. In addition, this module showed the strongest link to radiographic severity, correlating with Lund-Mackay (r = 0.60, p < 0.001), indicating that the coordinated immune gene expression best predicts disease burden. Conclusion Bulk transcriptomic network analysis identifies a dominant NP immune-activation program that reflects type 2 and mixed type 2/3 inflammation and shows the strongest association with radiographic disease severity. This module-level signal better captures disease burden than individual biomarkers and underscores coordinated epithelial—immune interactions–highlighting SYK/BTK signaling and integrin/ICAM1-mediated adhesion/migration alongside epithelial remodeling–as key drivers of polyp progression. Funding Source R01 AI134952, R01 DC016645, CRISP2 P01 AI145818. Topic Categories Immune Mechanisms of Human Disease (HUM)