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 6

The microbial antigen specificity of human Th17 cells determines whether pro- or antiinflammatory effects are promoted by NaCl.

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The microbial antigen specificity of human Th17 cells determines whether...
(A) Human Th17 cells were sorted by flow cytometry, labeled with CFSE, and restimulated with autologous monocytes (2:1 ratio) that had been pulsed for 3 hours with S. aureus (DSM799) or C. albicans (SC5314) lysates before glutardehyde fixation as described previously (2). CFSElo Th17 cells were FACS sorted on day 4 and then cloned. The T cell clones were restimulated on days 12 to 14 with CD3 and CD28 for 48 hours and analyzed after a 5-day culture period in low- or high-NaCl conditions before intracellular staining and FACS analysis or ELISA of the culture supernatants. (B) Naive T cells were sorted as CD4+CD45RA+ T cells and stimulated with autologous monocytes that were pulsed with microbial lysates in the presence or absence of endogenously produced or recombinant IL-1β. CFSElo T cells were FACS sorted and cloned on day 9. The T cell clones were restimulated in low- or high-NaCl conditions as in A. The fold change of FoxP3 expression in high- versus low-NaCl conditions is shown. ctrl., control. An unpaired 2-tailed Student’s t test was used for comparisons between 2 groups. Circles indicate individual T cell clones.