Type 2 Inflammation-Biased Arachidonic Acid Metabolite Regulates Mucosal Remodeling of Chronic Rhinosinusitis With Nasal Polyps.

Abstract

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common inflammatory respiratory disease. Its eosinophilic subtype (ECRSwNP), characterized by pronounced type 2 inflammation, mucosal edema and stromal remodeling, presents particular therapeutic challenges. Emerging evidence suggests metabolic dysregulation may contribute to its pathogenesis, but the underlying mechanisms remain unclear. METHODS: Untargeted metabolomics was performed using plasma and nasal mucosa from mouse models of CRSwNP with type 2 inflammation; targeted metabolomics was applied to plasma from patients with CRSwNP and healthy controls. Murine models, primary cells derived from nasal polyps, and samples from patients who had received anti-IL-4Rα monoclonal antibody were used to evaluate the role of 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE] in CRSwNP. RESULTS: (1) Mechanistically: The arachidonate 15-lipoxygenase (ALOX15)-dependent metabolite 15(S)-HETE, derived from arachidonic acid and induced by interleukin (IL)-4 and IL-13, correlated with CRSwNP severity. 15(S)-HETE reduced transforming growth factor-β1 (TGF-β1) through peroxisome proliferator-activated receptor gamma (PPAR-γ) activation, thereby impairing collagen production and exacerbating mucosal edema. (2) Therapeutically: In mouse models of CRSwNP, ALOX15 inhibition improved mucosal remodeling, reduced polyp size, and attenuated type 2 inflammation. Post hoc analysis of a clinical trial demonstrated that anti-IL-4Rα treatment reversed this metabolic axis and improved mucosal remodeling. CONCLUSION: This work establishes the type 2 inflammation-ALOX15-15(S)-HETE-PPAR-γ axis as a key driver of impaired tissue remodeling in ECRSwNP through TGF-β1 suppression. These findings provide novel mechanistic insights into the inflammation-metabolism-remodeling interplay in CRSwNP and highlight promising therapeutic targets for this refractory condition.