Inflammatory Conditions Determine Glucocorticoid Effects on Spontaneous or Immunoglobulin-Induced Neutrophil Death.

INTRODUCTION

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 (IVIG) and IgA promote neutrophil death, offering potential therapeutic benefits in neutrophil-predominant diseases.

METHODS

Neutrophils isolated from healthy donors and patients with acute appendicitis, together with an ex vivo appendicitis tissue model, were used to evaluate the effects of IgA, IVIG, and dexamethasone on neutrophil survival and apoptosis.

RESULTS

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. Dexamethasone inhibited IVIG-induced neutrophil death in unprimed or granulocyte-macrophage colony-stimulating factor-primed cells, but not in lipopolysaccharide-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.

CONCLUSION

These findings highlight the context-dependent nature of dexamethasone's effects and underscore the importance of local inflammatory or microbial factors in therapeutic outcomes.