Identification of Inflammatory Endotypes by Clinical Characteristics and Nasal Secretion Biomarkers in Chronic Rhinosinusitis with Nasal Polyps.

INTRODUCTION: The emergency of biologics and surgical techniques targeting the specific inflammatory endotype in chronic rhinosinusitis with nasal polyps (CRSwNP) asks for efficient identification of patients with different endotypes. Although mucosal IL-4, IL-5, IL-13, and IgE have been used to define type 2 (T2) inflammation, the optimal one remains unclear. In this study, we aimed to determine the optimal anchor for T2 inflammation and identify clinical characteristics and nasal secretion biomarkers predicting different endotypes in CRSwNP. METHODS: Six mediators in sinonasal tissue and 36 mediators in nasal secretion samples were detected by the Bio-Plex suspension array system. Mucosal IFN-γ and IL-17A levels were used to define the T1 and T3 endotype, respectively. The efficacy of mucosal IL-4, IL-5, IL-13, and IgE to define the T2 endotype was compared. The power of clinical characteristics and nasal secretion biomarkers to predict the T1, T2, and T3 endotype was analyzed. RESULTS: Among mucosal IL-4, IL-5, IL-13, and IgE, IL-13 was the best one to coincide with the expression of other T2 biomarkers. A combination of atopy, facial pain symptom score, ethmoid/maxillary computed tomography score ratio, and blood eosinophil percentage had a moderate predictive performance for T2 endotype (area under the receiver operating curve [AUC] = 0.815), comparable to that of nasal secretion IL-5 (AUC = 0.819). For the T3 endotype, nasal secretion IL-1Rα identified it with an AUC value of 0.756. No efficient marker for the T1 endotype was found. CONCLUSION: IL-13 is a primary anchor for the T2 endotype in CRSwNP. Clinical characteristics and nasal secretion biomarkers are helpful for identifying the T2 and T3 endotype of CRSwNP.

Perturbated glucose metabolism augments epithelial cell proinflammatory function in chronic rhinosinusitis.

BACKGROUND: Glucose concentrations are increased in nasal secretions in chronic rhinosinusitis (CRS). However, the glucose metabolism and its contribution to disease pathogenesis in CRS remain unexplored. OBJECTIVES: We sought to explore the glucose metabolism and its effect on the function of nasal epithelial cells in CRS with and without nasal polyps (CRSwNP and CRSsNP). METHODS: Glucose metabolites were detected with mass spectrometry. The mRNA levels of glucose transporters (GLUTs), metabolic enzymes, and inflammatory mediators were detected by quantitative RT-PCR. The protein expression of GLUTs was studied by immunofluorescence staining, Western blotting, and flow cytometry. Glucose uptake was measured by using fluorescent glucose analog. Human nasal epithelial cells (HNECs) were cultured. Bioenergetic analysis was performed with Seahorse XF analyzer. Gene expression in HNECs was profiled by RNA sequencing. RESULTS: Increased glucose concentrations in nasal secretions was confirmed in both CRSsNP and CRSwNP. GLUT4, GLUT10, and GLUT11 were abundantly expressed in HNECs, whose expression was upregulated by inflammatory cytokines and D-glucose and was increased in CRS. Glucose uptake, glycolysis and tricarboxylic acid cycle metabolites, metabolic enzymes, and extracellular acidification rate and oxygen consumption rates were increased in HNECs in CRSsNP and CRSwNP, with a predominant shift to glycolysis. HNECs treated with high-level apical D-glucose showed enhanced glucose uptake, predominant glycolysis, and upregulated production of IL-1α, IL-1ß, TNF-α, CCL20, and CXCL8, which was suppressed by 2-deoxy-D-glucose, an inhibitor of glycolysis. CONCLUSIONS: Increased glucose in nasal secretions promotes glucose uptake and predominant glycolysis in epithelial cells, augmenting the proinflammatory function of epithelial cells in CRS.