Salt generates antiinflammatory Th17 cells but amplifies pathogenicity in proinflammatory cytokine microenvironments
Julia Matthias, … , Thomas Korn, Christina E. Zielinski
Julia Matthias, … , Thomas Korn, Christina E. Zielinski
Published June 2, 2020
Citation Information: J Clin Invest. 2020;130(9):4587-4600. https://doi.org/10.1172/JCI137786.
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Research Article Immunology Inflammation

Salt generates antiinflammatory Th17 cells but amplifies pathogenicity in proinflammatory cytokine microenvironments

Abstract

Th cells integrate signals from their microenvironment to acquire distinct specialization programs for efficient clearance of diverse pathogens or for immunotolerance. Ionic signals have recently been demonstrated to affect T cell polarization and function. Sodium chloride (NaCl) was proposed to accumulate in peripheral tissues upon dietary intake and to promote autoimmunity via the Th17 cell axis. Here, we demonstrate that high-NaCl conditions induced a stable, pathogen-specific, antiinflammatory Th17 cell fate in human T cells in vitro. The p38/MAPK pathway, involving NFAT5 and SGK1, regulated FoxP3 and IL-17A expression in high-NaCl conditions. The NaCl-induced acquisition of an antiinflammatory Th17 cell fate was confirmed in vivo in an experimental autoimmune encephalomyelitis (EAE) mouse model, which demonstrated strongly reduced disease symptoms upon transfer of T cells polarized in high-NaCl conditions. However, NaCl was coopted to promote murine and human Th17 cell pathogenicity, if T cell stimulation occurred in a proinflammatory and TGF-β–low cytokine microenvironment. Taken together, our findings reveal a context-dependent, dichotomous role for NaCl in shaping Th17 cell pathogenicity. NaCl might therefore prove beneficial for the treatment of chronic inflammatory diseases in combination with cytokine-blocking drugs.

Authors

Julia Matthias, Sylvia Heink, Felix Picard, Julia Zeiträg, Anna Kolz, Ying-Yin Chao, Dominik Soll, Gustavo P. de Almeida, Elke Glasmacher, Ilse D. Jacobsen, Thomas Riedel, Anneli Peters, Stefan Floess, Jochen Huehn, Dirk Baumjohann, Magdalena Huber, Thomas Korn, Christina E. Zielinski

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Figure 2

Human Th17 cells acquire antiinflammatory functions upon restimulation in high-NaCl conditions.

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Human Th17 cells acquire antiinflammatory functions upon restimulation i...
(A) CD4+CD14–CD45RA–CCR6+CCR4+CXCR3– Th17 cells were sorted by flow cytometry from fresh human PBMCs as T cells and stimulated for a total culture period of 5 days in high- or low-NaCl conditions with CD3 and CD28 mAbs (48 hours plate-bound). Results for intracellular staining and FACS analysis on day 5 following PMA and ionomycin restimulation are shown. A representative FACS plot and cumulative data with each circle representing an individual donor are shown. (B) Intracellular staining for transcription factors followed by FACS analysis of T cells isolated and stimulated for 5 days with CD3 and CD28 mAbs (48 hours plate-bound). Top panel: Circles indicate individual blood donors. Bottom panel: Change in transcription factor expression in T cells stimulated in high- versus low-NaCl conditions (n = 3–4). (C) qRT-PCR analysis of Th17 cells stimulated as in A (n = 3–6). A 2-tailed Student’s t test was performed for comparisons of high- versus low-NaCl conditions; P < 0.05 for each of the transcripts shown. (D) GSEA for Treg-associated genes (GEO GSE18893) in Th17 cells cultured in low- or high-NaCl conditions for 5 days (48 hours CD3/CD28 mAbs). (E) T cell clones were generated from CD4+CD14–CD45RA–CCR6+CCR4+CXCR3– T cells, which were enriched for Th17 cells, and then restimulated in low or high NaCl concentrations, as in A. Intracellular staining and FACS analysis are shown. A representative FACS plot and cumulative data are shown. Each circle represents a separate T cell clone. A 2-tailed Student’s t test was used for comparisons between 2 groups (A–C, and E).