High Dietary Salt Aggravates Experimental Neuroinflammation in Mice Via Induction of Th17 Cells (S50.003)

Abstract

OBJECTIVE: To explore if salt-load may influence pathomechanisms of multiple sclerosis (MS), we investigated effects of a high salt diet (HSD) in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis (EAE).

BACKGROUND: Over the past half-century, there has been a marked increase in the incidence of MS that may be driven by changes in the environment. Excess salt (NaCl) uptake could be a contributing factor as it increases along with consumption of “western diet” and processed food in developed countries, where MS incidence is high.

DESIGN/METHODS: After induction of EAE, C57BL/6 mice were fed on a HSD (4.0% NaCl) or normal diet (0.4% NaCl). Histological and immunological analyses were performed to dissect underlying mechanisms of action.

RESULTS: HSD led to earlier onset and aggravation of EAE as well as increased inflammatory infiltration of macrophages/microglia and T cells in spinal cord lesions (n=12 p.g., p<0.05). Analysis of gene expression revealed a shift towards Th17 helper T cell driven autoimmunity by HSD. Expression of IL-17A and the transcription factor RORgt, but not interferon-gamma or T-bet were elevated in the spleen (n=5-6 p.g. p<0.05) and spinal cord (n=5-6 p.g. p<0.05). In vitro, restimulation of MOG primed splenocytes from mice on a HSD led to increased expression of IL-17 and Th17 signature genes. In T cell polarization assays in vitro, increasing the culture NaCl concentration by 40 mM did not influence Th1 or Th2 polarization, but boosted Th17 cell polarization up to 10-fold (n=6-11 p.g. p<0.001). This process involved p38 dependent pathways in vitro and in vivo as demonstrated by pharmacological inhibition (SB202190, p<0.01) and genetic ablation in a conditional knockout mouse model (n=6 p.g., p<0.01).

CONCLUSIONS: Our findings demonstrate that a high salt diet boosts Th17 responses thus exacerbating autoimmune neuroinflammation. Excess sodium uptake may constitute a new dietary factor possibly influencing complex autoimmune diseases like MS.

Disclosure: Dr. Linker has received personal compensation for activities with BayerVital, Biogen Idec, NovartisPharma, Merck Serono, and TEVA Pharma. Dr. Linker has received research support from BayerVital, Biogen Idec, NovartisPharma, Merck Serono, and TEVA Pharma. Dr. Manzel has nothing to disclose. Dr. Kleinewietfeld has received royalty payments from Stemcell-Technologies. Dr. Hafler has received personal compensation for activities with Wyeth, Beckman Coulter, and Novartis. Dr. Muller has nothing to disclose.