ALOX15-driven ω-6 fatty acid metabolism promotes type 2 inflammation in eosinophilic chronic rhinosinusitis with nasal polyps.

BACKGROUND

Local lipid metabolism contributes to immune homeostasis in the nasal mucosa and the pathogenesis of chronic rhinosinusitis. However, lipid mediator networks underlying eosinophilic chronic rhinosinusitis (ECRS) remain poorly defined.

OBJECTIVE

To characterize fatty acid-derived lipid mediator profiles in nasal polyps (NPs) from patients with and without ECRS and identify pathways associated with eosinophilic inflammation.

METHODS

Lipidomic profiling was performed using LC-MS/MS on NP tissues from patients with ECRS (n = 4) and without ECRS (n = 4). A total of 158 ω-6 and ω-3 fatty acid-derived lipid mediators were quantified. Arachidonate 15-lipoxygenase (ALOX15) pathway activity was evaluated by quantitative PCR and ELISA.

RESULTS

ECRS NPs displayed a distinct lipidomic signature compared with non-ECRS NPs. ECRS NPs exhibited increased levels of proinflammatory ω-6 fatty acid metabolites, including 15-hydroxyeicosatetraenoic acid (15-HETE) and 13-hydroxyoctadecadienoic acid, along with elevated ALOX15 pathway products and higher ALOX15 mRNA expression. Anti-inflammatory specialized proresolving mediators, such as lipoxin A4, were also elevated within the ω-6 pathway, and lipoxin A4 levels correlated with 15-HETE levels. These patterns indicate the concurrent activation of pro- and anti-inflammatory pathways, with a predominance of ALOX15-driven ω-6 metabolites in ECRS. In contrast, the ω-3 fatty acid pathway showed only modest increases in 14,15-DiHETE and resolvin D2, suggesting a limited compensatory resolution response compared with the robust ALOX15-dependent ω-6 activity.

CONCLUSIONS

ECRS NPs exhibit a skewed lipid mediator profile characterized by enhanced ALOX15-dependent ω-6 metabolism and insufficient resolution activity. This imbalance may underlie persistent type 2 inflammation in ECRS and suggests that targeting the 15-lipoxygenase pathway may offer therapeutic benefits.