A pinch more salt in macrophages

Hucke S, Eschborn M, Liebmann M, Herold M, Freise N, Engbers A, Ehling P, Meuth SG, Roth J, Kuhlmann T, Wiendl H, Klotz L. Sodium chloride promotes pro-inflammatory macrophage polarization thereby aggravating CNS autoimmunity. J Autoimmun. 2015. pii: S0896-8411(15)30052-4.

The increasing incidence in Multiple Sclerosis (MS) during the last decades in industrialized countries might be linked to a change in dietary habits. Nowadays, enhanced salt content is an important characteristic of Western diet and increased dietary salt (NaCl) intake promotes pathogenic T cell responses contributing to central nervous system (CNS) autoimmunity. Given the importance of macrophage responses for CNS disease propagation, we addressed the influence of salt consumption on macrophage responses in CNS autoimmunity. We observed that EAE-diseased mice receiving a NaCl-high diet showed strongly enhanced macrophage infiltration and activation within the CNS accompanied by disease aggravation during the effector phase of EAE. NaCl treatment of macrophages elicited a strong pro-inflammatory phenotype characterized by enhanced pro-inflammatory cytokine production, increased expression of immune-stimulatory molecules, and an antigen-independent boost of T cell proliferation. This NaCl-induced pro-inflammatory macrophage phenotype was accompanied by increased activation of NF-kB and MAPK signaling pathways. The pathogenic relevance of NaCl-conditioned macrophages is illustrated by the finding that transfer into EAE-diseased animals resulted in significant disease aggravation compared to untreated macrophages. Importantly, also in human monocytes, NaCl promoted a pro-inflammatory phenotype that enhanced human T cell proliferation. Taken together, high dietary salt intake promotes pro-inflammatory macrophages that aggravate CNS autoimmunity. Together with other studies, these results underline the need to further determine the relevance of increased dietary salt intake for MS disease severity.

It has been reported that a high salt diet can induce higher levels of autoimmunity and it has been reported that a high sodium diet can make autoimmunity worse in some mouse strains. This is on of the hottest recent papers in MS research according to Altmetrics

What does an increase of abit of a non-linear scale of EAE or onset abit earlier in sub optimal EAE (controls are a 1 compared to the usual 3 in most other experiments) mean to someone with MS. 

Does it equate to worse disease? I guess we will see. 

In this new paper the salt story continues and this new study 
indicates  that macrophages are also more juiced up in high salt diets.

If you have more disease this is because you have more infiltration into the CNS and so you have more T cells in there and more macrophages in there, so chicken and egg. In this study the authors also find that macrophages from high salt diet are more stimulated as has been found for T cells, where it drives pathogenic Th17 (click) (click) apparently because  it blocks the suppressive effect of T regulatory cells (click) and also blocks the formation of M2 type macrophages that are the type of cells that are reported to promote re myelination (click)


Some authors argue (click) on "data generated by the world health organization (WHO), a direct correlation between salt intake and prevalence of MS is not apparent in the broad sense. Countries such as China and Japan, which traditionally have the highest salt intake (confirmed in a large number of studies) due to generous addition of salt during cooking and dietary regulars such as soy and miso, also show some of the lowest rates of MS prevalence in the population (< 0.5 per 100 000 of the population). Conversely, the United States of America and the United Kingdom, which both recorded an MS prevalence of > 100 per 100 000 of the population, have relatively low salt intakes compared to these Asian countries. A simple 'one-to-one' overlap was of course unlikely, but one cannot exclude the possibility that for individuals predisposed to autoimmunity through various susceptibility loci, increased salt intake may in fact aggravate their clinical symptoms. This is of course a very attractive concept, as some benefit to patients may be realized at minimal expense and with the greatest of ease simply by avoiding foods rich in salt content".
We already know that too much salt carriers health risks and one can modify diets. Is this why the North South (Sun-light) MS gradient (higher in North than the South) that used to exist in the USA is disappearing? Is it that the Southerners are eating more salt and it has nothing to do with cars and movement of people.

"One major question now is the physiological underpinning of their findings. Apparently increased dietary salt intake does not render higher concentrations of sodium in the blood or lymph nodes, where T cells usually dwell (click). But does this act via the gut
environment where elevated levels of salt might be sensed?  

Is it that the salt content influences the gut microbiome, so just like you get some fish living in freshwater and others that live in salt water and some can live in both. Is this where an effect occurs.

Given that a low-salt diet poses no safety concerns, such studies can be initiated without delay" and indeed they have been

The Effect of Dietary Salt Intake on Immune Function in Patients With Multiple Sclerosis (NCT02282878). Newly Diagnosed MS patients randomized to high sodium first diet will receive 2 weeks of controlled high sodium diet followed by a 1 week washout and 2 weeks of low sodium diet. Newly Diagnosed MS patients randomized to low sodium first diet will receive 2 weeks of controlled low sodium diet followed by a 1 week washout and 2 weeks of high sodium diet. The aim is to look at the influence of dietry salt on Th17 responses.

One question that keeps slipping the ediors/referees minds from the animal experiments is what is the relevance of this amount of salt given to mice when compared to humans. No dose response has been done in the mice experiments, so what does to you use in humans. The human equivalent dose to that used in mice calculated at 660g of salt a day, which is abit higher than 8-15g/day taken by humans. Given that 18g in water of salt makes humans vomit,  but mice and rats can't vomit, its alot.  

So should such data be taken with a pinch of salt? Dr. Pryce was brave to ask the question in public.....that's the end to his chances of career in Yale. Would you get the same result with less salt?, would you see an effect if you had typical full blown EAE?

But does it matter you say? 

As salt is the real deal as a study has already been done (NCT01846234).
Farez MF, Fiol MP, Gaitán MI, Quintana FJ, Correale J. Sodium intake is associated with increased disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2015; 86:26-31.

Recently, salt has been shown to modulate the differentiation of human and mouse Th17 cells and mice that were fed a high-sodium diet were described to develop more aggressive courses of experimental autoimmune encephalomyelitis. However, the role of sodium intake in multiple sclerosis (MS) has not been addressed. We aimed to investigate the relationship between salt consumption and clinical and radiological disease activity in MS.

METHODS:We conducted an observational study in which sodium intake was estimated from sodium excretion in urine samples from a cohort of 70 relapsing-remitting patients with MS who were followed for 2 years. The effect of sodium intake in MS disease activity was estimated using regression analysis. We then replicated our findings in a separate group of 52 patients with MS.
RESULTS: We found a positive correlation between exacerbation rates and sodium intake in a multivariate model adjusted for age, gender, disease duration, smoking status, vitamin D levels, body mass index and treatment. We found an exacerbation rate that was 2.75-fold (95% CI 1.3 to 5.8) or 3.95-fold (95% CI 1.4 to 11.2) higher in patients with medium or high sodium intakes compared with the low-intake group. Additionally, individuals with high-sodium intake had a 3.4-fold greater chance of developing a new lesion on the MRI and on average had eight more T2 lesions on MRI. A similar relationship was found in the independent replication group.
CONCLUSIONS: Our results suggest that a higher sodium intake is associated with increased clinical and radiological disease activity in patients with MS.

So avoid too much salt as we know it is bad for your health but likewise you need it too. What will be the effect of salt on the action of a DMT because it a placebo-controlled trial should be difficult to do in RRMS?

Labels: