Peritoneal dialysate-range hypertonic glucose promotes T-cell IL-17 production that induces mesothelial inflammation
| Autor: | Hermann Haller, David de Luca, Sibylle von Vietinghoff, Marcus Hiss, Nelli Shushakova, Svenja Gaedcke, Martin Reinhardt, Alexandra Helmke, Michael S. Balzer, Anne M. Hüsing, Immo Prinz, Nicolas Brauns |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty T cell Chemokine CXCL1 Immunology Cell Biology Epithelium 03 medical and health sciences Peritoneal cavity Mice 0302 clinical medicine Downregulation and upregulation RAR-related orphan receptor gamma Internal medicine medicine Immunology and Allergy Animals Humans Inducer Cells Cultured Chemokine CCL2 Inflammation Interleukin-6 Interleukin-17 Middle Aged Mitochondria Up-Regulation Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Endocrinology Glucose Tonicity Th17 Cells Female Interleukin 17 Peritoneum Reactive Oxygen Species Mannose Peritoneal Dialysis 030215 immunology |
| Zdroj: | European journal of immunologyReferences. 51(2) |
| ISSN: | 1521-4141 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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