Immune hyperactivity in hemodialysis patients is associated with interferon gamma-induced trained immunity

Hemodialysis patients experience persistent inflammation marked by pro-inflammatory monocytes. We hypothesized that the hyper-responsiveness of innate immune cells in these patients is facilitated by trained immunity, a form of innate immune memory. Hemodialysis patients displayed elevated monocyte counts, and isolated peripheral blood mononuclear cells showed significantly heightened cytokine responses after Toll-like receptor stimulation, both indicative of trained immunity. Importantly, plasma interferon gamma (IFN-γ) concentrations positively correlated with cytokine responses. Whole-genome RNA-sequencing revealed enrichment of interferon response pathways, particularly in patients whose monocytes exhibited the most pronounced cytokine production upon restimulation. In vitro experiments confirmed that trained immunity induction depends on IFN-γ, produced by CD4⁺ T cells. Our findings demonstrate that hemodialysis patients display a dysregulated immune response characterized by trained immunity and that this might be mediated by IFN-γ. These insights suggest that targeting IFN-γ could be a promising strategy to mitigate damaging immune hyperactivity in dialysis patients.