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

Abstract

T helper 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, anti-inflammatory Th17 cell fate in human T cells in vitro. The p38/MAPK pathway, involving NFAT5 and SGK1, regulated FoxP3 and interleukin (IL)-17Aexpression in high-NaCl conditions. The NaCl-induced acquisition of an anti-inflammatory 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 pro-inflammatory and TGF--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 cytokineblocking drugs.

Cytokine‐regulated Th17 plasticity in human health and diseases

“…In human memory Th17 cells, NaCl, in the presence of TGF‐β, promotes their immunoregulatory function through the NFAT5‐SGK1‐FoxP3 pathway. However, in pro‐inflammatory conditions and the absence of TGF‐β, NaCl boosts pro‐inflammatory cytokine production in both human and mouse Th17 cells and promotes pathogenicity in an EAE model 108 . Also, oxygen concentrations appear to impact on Th17 cell phenotype, as mouse Th17 cells cultured in hypoxic conditions (1% O 2 ) produced significantly more IL‐10 than Th17 cells cultured at 21% O 2.…”

High-salt diet suppresses autoimmune demyelination by regulating the blood–brain barrier permeability

“…For example, in the ileal lamina propria, T H 17 cells may be reeducated to acquire an anti-inflammatory phenotype ( 13 ). Also, a recent report suggests that human T H 17 cells (CD4 + CD14 − CD45RA − CCR6 + CCR4 + CXCR3 − ) cultured in vitro under high-salt conditions assume an anti-inflammatory phenotype characterized by the up-regulation of Foxp3 and IL-10 ( 14 ). However, we neither found changes in the Foxp3 expression ( Fig.…”

Host Immune Defense upon Fungal Infections with Mucorales: Pathogen-Immune Cell Interactions as Drivers of Inflammatory Responses

“…Microenvironmental factors other than cytokines (e.g., oxygen, lipids, glucose, microbial products, or salts) are involved in the differentiation of immune cells, which might impact their capacity to control fungal infections [ 70 , 71 , 72 , 73 , 74 ]. For example, sodium chloride (NaCl) is usually found in peripheral tissues and promotes differentiation of human and murine Th17 cells with anti-inflammatory properties [ 70 , 75 ]. The NaCl effect is infection-dependent as shown by the promotion of anti-inflammatory functions in Staphylococcus aureus -specific Th17 cells but not in Candida -specific Th17 cells [ 75 ].…”

“…For example, sodium chloride (NaCl) is usually found in peripheral tissues and promotes differentiation of human and murine Th17 cells with anti-inflammatory properties [ 70 , 75 ]. The NaCl effect is infection-dependent as shown by the promotion of anti-inflammatory functions in Staphylococcus aureus -specific Th17 cells but not in Candida -specific Th17 cells [ 75 ]. On the contrary, this NaCl anti-inflammatory effect was reversed by the cytokine IL-1β.…”