Tuesday, 24 November 2015

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?

8 comments:

  1. This comment has been removed by a blog administrator.

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    1. Sorry I deleted you post by accident when trying to launch it using a phone. If you want to post again or maybe ProfG can repost this comment.

      I remember asking How can we scale. SImple. The calculation is there for all to read.
      Does this gives a blood level equivalent to the in vitro experiments?

      I can't remember your point of the comment on Prof Halfer, one of the most respected human immunologists., I doubt he was doing the animal experiments as the mice came from Germany not USA if I remember the methods section.

      Not sure what you point is about what allows us to question anything?

      Is it how dare you question?....... That is what scientists do. If this is the level of the comment it is best it stays deleted

      Item 19 of ARRIVE guidelines is discuss translatability.

      You may soon be asked to remove more salt from your diet. First question you should ask is..What is the evidence to support this?

      Delete
    2. Anonymous has left a new comment on your post "A pinch more salt in macrophages":

      How can you simply scale up the salt dose from mice to man? Prof Hafler disagrees with you on this; he claims the current excess daily intake of salt in man is sufficient to drive abnormal T-cell responses. At least they have some data to support their claims. Do you have any data to support your claims?

      Delete
    3. The data in the figure shows that there may not be reproducibility dependent on sex and genetics. The truth will be out as there will be a sea of repeats

      As I say we already know too much salt is bad for you.

      Delete
  2. Interestingly, sometime back my fiance' posted here she had heard there were 15,000 confirmed cases of MS in Western NY State.

    MAP (https://search.yahoo.com/yhs/search?p=wstern+nyh+map&ei=UTF-8&hspart=mozilla&hsimp=yhs-001)

    I recently managed to obtain a real number, 15,000. Also explains why Pharma places alot of events into the region. As she said (is telling me) nearly everyone here knows someone with MS or has had MS.

    My mother was a Registered Nurse and we are talking 1960's / 70's she worked with many many MS patients and say's even back then there were just loads of MS cases here. Surely, Vitamin D as an impact (we can get considerable clouds due to proximity to the Great Lakes). The area before the USA managed loose manufacturing was heavily industrialized. Thus many a toxic ground area though many have now been "cleaned up" or encapsulated. But additionally much of western NY was subject to "acid rain" due to industries westward (Detroit etc) with prevailing winds carrying airborne matter over the great lakes where it was theorized would seed in clouds and dump on the Western NY and upper Pennsylvania regions.

    Whilst there is not proof positive of genetics and MS it is probably there and/or association with other disorders. No studies I am aware of focus on MS or other autoimmune disorders in the Great Lakes regions (US and Canada) in attempting attain numbers, obviously someone already knows as people past and present are treated, heads counted.

    In fact, industrialization here around the great lakes and subsequent chemicals also found their way to the UK. There were essentially three mechanisms back in the late 60's and 70's for dealing with the pollutant matters. 1. filtering, remove what they could. 2. Super heating the airborne contaminants, this resulted in some changing to more inert forms. 3. The super heating was coupled with essentially very high speed focused exhaust. Thus blowing the materials higher into the atmosphere. Kodak did this for example. If the Jetstream happened to be over the area which is not unusual.... The pollutants get carried much much farther.

    Regardless... It is unusual that rates of MS are significant high around the great lakes and that families have MS. Mothers, daughters which must be more than just bad luck.

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  3. You can even be completely plausible that increased salt intake in the diet raise the activity of the disease, too much salt is a villain to health as a whole by just being pro-inflamatóriom but so too are red meat and sugar. Perhaps the relationship is actually in changing the intestinal microbiome ... Now I always had a diet low intake of salt and sugar, because my family has a history of cardiovascular problems, not MS, and I am also former athlete, so whenever cared and continued taking care of my food ... but I had recurring mononucleosis ... I bet they look more to the action of viruses and bacteria in genetically susceptible to disease ...
    PS: nothing to do with MS but here in Brazil we're having a Microcephaly outbreak in babies born in the Northeast region of the country, probably associated with infection of mothers by Zika virus, transmitted by the Aedes aegypti. This virus is not native to the country, it was probably brought by migratory waves coming from the Caribbean and Africa. There are now 739 confirmed cases of microcephaly in babies born last month ...

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  4. My primary school, was next to a medical supplies factory. We were told it was a rubber company. It emitted acrid smoke from it's chimneys every day which made us feel sick. I remember playing cricket on the roof of my school with my West Indian fast bowling schoolmates and I scored a six straight into the factory. That's how close we were to pollutants. We have always wondered how many kids ended up with serious illnesses.

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  5. The interezting thing is that we get augmentation with excessive salt it is interesting that it is not inhibition that you may expe tex ic the animalz were being stressed

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