Metabolic Reprogramming Drives a Refractory Mixed Th2/Th17 Endotype in Chronic Rhinosinusitis with Nasal Polyps

Area of Science:

• Immunology
• Metabolomics
• Rhinology

Background:

• Chronic rhinosinusitis with nasal polyps (CRSwNP) shows diverse inflammatory patterns.
• Asian populations often present with mixed, non-T2, or neutrophilic CRSwNP endotypes.
• A mixed Th2/Th17 profile in CRSwNP can lead to treatment resistance.

Purpose of the Study:

• To investigate metabolic and structural differences in CRSwNP with a mixed Th2/Th17 endotype.
• To characterize the prognostic implications of this distinct CRSwNP endotype.

Main Methods:

• Integrated transcriptomic and metabolomic analyses on nasal tissues from CRSwNP patients and controls.
• Stratification of patients into High-Th17 and Low-Th17 endotypes using gene signatures.
• Comparison of immunometabolic profiles, barrier remodeling markers, and surgical outcomes across endotypes.

Main Results:

• The High-Th17 endotype was identified in 30.8% of CRSwNP patients, showing similar clinical markers (IgE, eosinophils) to Th2-dominant disease.
• Patients with concurrent Th2/Th17 elevation ('Double-High') had better postoperative disease control (48%) than 'Pure Th2' (25%).
• High-Th17 CRSwNP exhibited altered metabolism (aerobic glycolysis) and lipid mediator accumulation, correlating with squamous metaplasia and tissue remodeling.

Conclusions:

• The High-Th17 endotype in CRSwNP presents a mixed inflammatory state with overlapping clinical features but distinct biological pathways compared to T2 disease.
• The link between mixed Th2/Th17 inflammation, enhanced glycolysis, and squamous metaplasia offers a molecular basis for understanding treatment-refractory CRSwNP.
• Further research is needed to validate these findings mechanistically.