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 1

NaCl promotes the Th17 cell program in human effector memory Th cells independently of polarizing cytokines.

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NaCl promotes the Th17 cell program in human effector memory Th cells in...
(A–C) Human effector memory Th cells were FACS sorted from fresh human PBMCs as CD4+CD14–CD45RA–CCR7– T cells and stimulated for a total culture period of 5 days in low- or high-NaCl conditions with CD3 and CD28 mAbs (48 hours plate-bound). (A) Intracellular staining and FACS on day 5 after PMA and ionomycin restimulation for 5 hours. FACS staining of an individual experiment (left) and cumulative data are shown. Each circle indicates an individual donor. gMFI, geometric MFI; max, maximum. (B) ELISA analysis of cell culture supernatants analyzed on day 5 after stimulation with PdBU and CD3 mAb for 8 hours (n = 3). (C) Transcriptome analysis and GSEA (GSE52260) of genes related to the Th17 signature in Th17 cells stimulated as in A (67). (D) Skin CD3+ T cells were isolated from human abdominal skin by overnight collagenase digestion followed by FACS sorting. The cells were stimulated for 48 hours with CD3 and CD28 mAbs in low- or high-NaCl conditions followed by intracellular cytokine staining after PMA and ionomycin restimulation. A representative experiment (left) and cumulative data are shown (middle). ELISA analysis (right) of cell culture supernatants from skin CD3+ T cells restimulated with PdBU and CD3 mAbs for 8 hours after 48 hours of CD3 and CD28 mAb stimulation in low- and high-NaCl conditions. Data were normalized to 20,000 T cells. Each circle indicates an individual donor. (E) FACS analysis performed as in A in the absence or presence of Th17-polarizing cytokines. The data are representative of 3 donors. (A, B, and D) A 2-tailed, paired Student’s t test was performed for comparisons between 2 groups.