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

Hemodialysis patients experience persistent inflammation due to increased production of pro-inflammatory monocytes. We hypothesized that the persistent hyper-responsiveness of innate immune cells in these patients is driven by trained immunity, a form of innate immune memory. This observational study aimed to investigate the presence of trained immunity responses in hemodialysis patients and to elucidate the molecular mechanisms underlying it. We profiled innate immune cell subsets by flow cytometry and cytokine responses of hemodialysis patients and healthy controls following ex vivo stimulation of peripheral blood mononuclear cells with Toll-like receptor (TLR) agonists. Plasma concentrations of inflammatory markers were assessed using the Olink Proximity Extension Assay, while whole-genome RNA sequencing was performed on circulating monocytes to identify genes associated with trained immunity. In vitro assays were conducted to explore the role of interferon gamma (IFN-γ) in mediating trained immunity. Hemodialysis patients displayed elevated monocyte counts and their cells showed significantly heightened cytokine responses to TLR stimulation, indicative of trained immunity. Importantly, plasma IFN-γ concentrations positively correlated with these cytokine responses. Gene expression analysis 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.