Exaggerated epithelial cell glycolysis promotes neutrophilic inflammation in chronic rhinosinusitis
Published: October 27, 2022
Chronic rhinosinusitis (CRS) is an inflammatory condition of the paranasal sinuses and includes two clinical phenotypes, CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). The pathophysiology of CRS is complicated and orchestrated by immune cells (eosinophils, neutrophils, and lymphocytes, etc.) and structural cells (epithelial cells and stromal cells, etc.). Recently, the advanced understanding of the pathogenesis of type 2 responses and eosinophilic inflammation in CRS has led to the successful development of biologics targeting type 2 and eosinophilic inflammation in CRS. However, the mechanisms underlying the neutrophilic inflammation in CRS remain poorly elucidated, which is associated with glucocorticoid resistance and refractory disease state in patients with CRS, and lack of target treatments. Nasal epithelial cells are active driver of inflammation by releasing an array of cytokines, chemokines, and damage-associated molecular patterns. Nevertheless, the investigation of the regulation of their function in orchestrating inflammation in CRS is limited. Metabolism fuels diverse biological programs, ranging from development, proliferation, differentiation, and the effector functions performed by cells and tissues. Inflammatory activation can occur in the context of changes in cellular metabolism. Elevated glucose concentrations in nasal secretions were reported in patients with CRS. However, it is unclear whether increased glucose in airway surface liquid affects metabolism of nasal epithelial cells, and subsequently modifies their function and shapes the inflammatory response in CRS.
In a recent study published in The Journal of Allergy & Clinical Immunology (JACI), Chen and colleagues investigated glucose metabolism and its effects on pro-inflammatory function in nasal epithelial cells in CRS. The researchers studied the metabolites of glucose in the nasal epithelial cells by the targeted metabolic mass spectrometry. The mRNA expression of glucose transporters (GLUTs), metabolic enzymes, and inflammatory mediators were detected by quantitative RT-PCR. The nasal epithelial cells were cultured with an air-liquid interface method. Glucose uptake was explored by flow cytometry. The effects of nasal secretion glucose on the metabolism of epithelial cells were studied with seahorse XF24 analyzer, and the gene expression was profiled by RNA sequencing. 2-Deoxy-D-glucose, a glycolysis inhibitor, was used to study the effect of glycolysis inhibition on epithelial cell function.
The authors found increased glucose concentrations in nasal secretions from both CRSsNP and CRSwNP patients. GLUT4, GLUT10 and GLUT11 were abundantly expressed in nasal epithelial cells, whose expression was up-regulated by inflammatory cytokines and D-glucose, and was increased in patients with CRS. Glucose uptake, glycolysis and tricarboxylic acid cycle metabolites, relevant metabolic enzymes, and extracellular acidification rate and oxygen consumption rates were increased in nasal epithelial cells in patients with CRSsNP and CRSwNP, with a predominant shift to glycolysis. Normal nasal epithelial cells treated with high-level apical D-glucose showed enhanced glucose uptake, predominant glycolysis, and up-regulated production of IL-1α, IL-1β, TNF-α, CCL20 and CXCL8. Interestingly, IL-1β and TNF-α were able to enhance glucose uptake and glycolysis in nasal epithelial cells, suggesting a vicious feedback loop between inflammation and glucose metabolism reprogram in nasal epithelial cells in the pathogenesis of CRS. The authors found that the expression of IL-1α, IL-1β, TNF-α, CCL20 and CXCL8 was increased in epithelial cells in both CRSsNP and CRSwNP and correlated with tissue neutrophils. The levels of L-lactate, the major product of glycolysis, were associated with tissue neutrophil numbers, but not eosinophil numbers. This study further found that inhibition of glycolysis by 2-Deoxy-D-glucose down-regulated the production of inflammatory cytokines and chemokines in CRS-derived nasal epithelial cells, indicating a therapeutic potential of glycolysis inhibition in CRS.
Overall, the authors showed that glucose metabolism is enhanced in the nasal epithelial cells in both CRSsNP and CRSwNP patients, with a predominant shift to glycolysis. Increased glucose in airway surface liquid promotes glucose uptake, glycolysis, as well as pro-inflammatory gene expression in nasal epithelial cells, associating with neutrophil inflammation in both CRSsNP and CRSwNP. Inhibiting glycolysis in nasal epithelial cells may have potential therapeutic value to control neutrophilic inflammation in CRS.
The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.
Full Article
Graphical Abstract