Peritoneal dialysis (PD) employs hypertonic glucose to remove excess water and uremic waste. Peritoneal membrane failure limits its long-term use. T-cell cytokines promote this decline. T-cell differentiation is critically determined by the microenvironment. We here study how PD-range hypertonic glucose regulates T-cell polarization and IL-17 production. In the human peritoneal cavity, CD3(+) cell numbers increased in PD. Single cell RNA sequencing detected expression of T helper (Th) 17 signature genes RORC and IL23R. In vitro, PD-range glucose stimulated spontaneous and amplified cytokine-induced Th17 polarization. Osmotic controls l-glucose and d-mannose demonstrate that induction of IL-17A is a substance-independent, tonicity dose-dependent process. PD-range glucose upregulated glycolysis and increased the proportion of dysfunctional mitochondria. Blockade of reactive-oxygen species (ROS) prevented IL-17A induction in response to PD-range glucose. Peritoneal mesothelium cultured with IL-17A or IL17F produced pro-inflammatory cytokines IL-6, CCL2, and CX3CL1. In PD patients, peritoneal IL-17A positively correlated with CX3CL1 concentrations. PD-range glucose-stimulated, but neither identically treated Il17a(-/-) Il17f(-/-) nor T cells cultured with the ROS scavenger N-acetylcysteine enhanced mesothelial CX3CL1 expression. Our data delineate PD-range hypertonic glucose as a novel inducer of Th17 polarization in a mitochondrial-ROS-dependent manner. Modulation of tonicity-mediated effects of PD solutions may improve membrane survival.
- Helmke, A.
- Hüsing, A. M.
- Gaedcke, S.
- Brauns, N.
- Balzer, M. S.
- Reinhardt, M.
- Hiss, M.
- Shushakova, N.
- de Luca, D.
- Prinz, I.
- Haller, H.
- von Vietinghoff, S.
Keywords
- Animals
- Cells, Cultured
- Chemokine CCL2/immunology
- Chemokine CXCL1/immunology
- Epithelium/*immunology
- Female
- Glucose/*immunology
- Humans
- Inflammation/*immunology
- Interleukin-17/*immunology
- Interleukin-6/immunology
- Male
- Mannose/immunology
- Mice
- Mice, Inbred C57BL
- Middle Aged
- Mitochondria/immunology
- Peritoneal Dialysis/methods
- Peritoneum/*immunology
- Reactive Oxygen Species/immunology
- Th17 Cells/*immunology
- Up-Regulation/immunology
- *Th17 polarization
- *hypertonic glucose
- *peritoneal dialysis
- *peritoneal inflammation
- *reactive oxygen species