Neutrophil extracellular traps promote M1 macrophage polarization in gouty inflammation via targeting hexokinase-2

macrophage infiltration were observed in human gouty arthritis (GA). In vitro, MSU crystal-induced NETs or NET-associated histone H3 treatments modulated nod-like receptor protein 3 (NLRP3) inflammasome activation, M1 polarization, and metabolic changes in macrophages. These effects were eliminated by hexokinase-2 (HK-2) silencing. Moreover, NET formation and inflammation were significantly reduced in PAD4-/- GA mice. Pharmacological inhibition of NET formation with Cl-Amidine or NET degradation with DNase Ⅰ significantly reduced M1 polarization of macrophages and ameliorated inflammation in GA mice. In sum, MSU crystal-induced NETs promote M1 polarization and NLRP3 activation in macrophages via targeting HK-2. Cell-free DNA and histone H3 may be the driving elements behind the NET-induced M1 macrophage polarization, NLRP3 activation, and metabolic changes. Targeting NETs could be a potential therapeutic strategy for gout flare.