A review of the mechanisms linking Th2 immune storm to NETosis through neutrophil glycolytic activation.

The core metabolic mode of neutrophils is ATP generation, dominated by glycolysis, which is tailored to meet their demands for rapid response and short-term survival. The Th2 immune storm drives neutrophil metabolic reprogramming through inflammatory cytokines and hypoxia signals, leading to a burst in glycolysis (a "Warburg-like" state). This results in the upregulation of key rate-limiting enzymes, including Hexokinase 2 (HK2), Lactate Dehydrogenase A (LDHA), and Pyruvate Kinase M2 (PKM2), as well as lactate accumulation. Glycolysis induces the release of Neutrophil Extracellular Traps (NETs) through the PKM2-HIF-1α transcriptional complex and ATP-dependent chromatin remodeling. Although NETs can capture pathogens and activate immune responses, their excessive release triggers the emission of damage associated molecular patterns (DAMPs), ultimately driving disease chronicity. This forms a vicious cycle, driving persistent inflammation, tissue damage, and disease. This series of pathology processes driven by metabolic reprogramming constitutes the core mechanism of glucocorticoid resistance and chronic inflammation in allergic diseases. This review systematically summarizes the related metabolic foundations, providing new strategies for treatments targeting glycolysis or NETosis.