Science and Research

Peritoneal dialysate-range hypertonic glucose promotes T-cell IL-17 production that induces mesothelial inflammation

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
Publication details
DOI: 10.1002/eji.202048733
Journal: Eur J Immunol
Pages: 354-367 
Number: 2
Work Type: Original
Location: BREATH
Disease Area: PALI
Partner / Member: MHH
Access-Number: 32926407

DZL Engagements

chevron-down