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

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.

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.

(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.

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.