Transcriptomic analysis reveals novel mechanisms underlying neutrophil activation induced by high salt

Elevated sodium concentrations are commonly observed in tumors and sites of inflammation. Previous studies have shown that high salt levels modulate the phenotype and function of CD4+ and CD8+ T cells, regulatory T cells and macrophages. In this study, we performed transcriptomic studies that revealed profound alterations in the neutrophil transcriptome upon high salt exposure, with changes that significantly exceeded those triggered by conventional agonists. By integrating transcriptomic data with functional assays, our findings indicate that high salt-induced neutrophil activation involves mitochondrial ROS production, which subsequently activates p38 MAPK and engages FOS-, BTK-, and COX2-dependent pathways. Remarkably, the plasticity of the neutrophil transcriptome in response to high salt was further evidenced by the upregulation of genes typically associated with other cell types, including SEMG1, ICAM4, TRIM69, AREG, OSM, and TOB1, suggesting a broader role for neutrophils in different biological processes beyond their participation in innate immunity.