Inflammatory conditions determine glucocorticoid effects on spontaneous or immunoglobulin-induced neutrophil death

Neutrophils play a central role in the pathogenesis of inflammatory and autoimmune disorders. While glucocorticoids are potent anti-inflammatory agents, they are known to promote neutrophil survival, which may worsen neutrophil-driven conditions. In contrast, intravenous immunoglobulin and IgA promote neutrophil death, offering potential therapeutic benefits in neutrophil-predominant diseases. In this study, we found that dexamethasone effects on neutrophil survival and its interaction with IVIG-induced neutrophil death are differentially influenced by cytokines or microbial components, whereby dexamethasone inhibited IVIG-induced neutrophil death in unprimed or GM-CSF-, but not in LPS-primed cells. The effects of dexamethasone were mediated by glucocorticoid receptor signaling and genomic regulation, suppressing apoptotic and non-apoptotic death pathways. In an ex vivo model of appendicitis, despite dexamethasone’s pro-survival effects, neutrophils underwent significant death in response to IVIG or IgA. These findings highlight the context-dependent nature of dexamethasone’s effects and underscore the importance of local inflammatory or microbial factors in therapeutic outcomes.