Tuesday, 28 April 2015

Blocking microglial could this affect progression

Savarin C, Hinton DR, Valentin-Torres A, Chen Z, Trapp BD, Bergmann CC, Stohlman SA.Astrocyte response to IFN-γ limits IL-6-mediated microglia activation and progressive autoimmune encephalomyelitis.J Neuroinflammation. 2015;12(1):79. [Epub ahead of print
BACKGROUND:Therapeutic modalities effective in patients with progressive forms of multiple sclerosis (MS) are limited. In a murine model of progressive MS, the sustained disability during the chronic phase of experimental autoimmune encephalomyelitis (EAE) correlated with elevated expression of interleukin (IL)-6, a cytokine with pleiotropic functions and therapeutic target for non-central nervous system (CNS) autoimmune disease. Sustained IL-6 expression in astrocytes restricted to areas of demyelination suggested that IL-6 plays a major role in disease progression during chronic EAE.
METHODS:A progressive form of EAE was induced using transgenic mice expressing a dominant negative interferon-γ (IFN-γ) receptor alpha chain under control of human glial fibrillary acidic protein (GFAP) promoter (GFAPγR1Δ mice). The role of IL-6 in regulating progressive CNS autoimmunity was assessed by treating GFAPγR1Δ mice with anti-IL-6 neutralizing antibody during chronic EAE.
RESULTS:IL-6 neutralization restricted disease progression and decreased disability, myelin loss, and axonal damage without affecting astrogliosis. IL-6 blockade reduced CNS inflammation by limiting inflammatory cell proliferation; however, the relative frequencies of CNS leukocyte infiltrates, including the Th1, Th17, and Treg CD4 T cell subsets, were not altered. IL-6 blockade rather limited the activation and proliferation of microglia, which correlated with higher expression of Galectin-1, a regulator of microglia activation expressed by astrocytes.
CONCLUSIONS:These data demonstrate that astrocyte-derived IL-6 is a key mediator of progressive disease and support IL-6 blockade as a viable intervention strategy to combat progressive MS

Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory cytokine. IL-6 is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other tissue damage leading to inflammation. IL-6 also plays a role in fighting infection,. IL-6 role as an anti-inflammatory cytokine. IL-6 is an important mediator of fever and of the acute phase response. It is capable of crossing the blood-brain barrier and changing the body's temperature setpoint. In muscle and fatty tissue, IL-6 stimulates energy mobilization that leads to increased body temperature. IL-6 can be secreted by macrophages in response to specific microbial molecules, referred to as pathogen-associated molecular patterns (PAMPs). These PAMPs bind to an important group of detection molecules of the innate immune system, called pattern recognition receptors (PRRs), including Toll-like receptors (TLRs). These are present on the cell surface and intracellular compartments and induce intracellular signalling cascades that give rise to inflammatory cytokine production. IL-6 is responsible for stimulating acute phase protein synthesis, as well as the production of neutrophils in the bone marrow. It supports the growth of B cells and is antagonistic to regulatory T cells.

IL-6 signals through a cell-surface type I cytokine receptor complex consisting of the ligand-binding IL-6Rα chain (CD126), and the signal-transducing componentgp130 (also called CD130). CD130 is the common signal transducer for several cytokines including leukemia inhibitory factor (LIF), ciliary neurotropic factor,oncostatin M, IL-11 and cardiotrophin-1, and is almost ubiquitously expressed in most tissues. In contrast, the expression of CD126 is restricted to certain tissues. As IL-6 interacts with its receptor, it triggers the gp130 and IL-6R proteins to form a complex, thus activating the receptor. These complexes bring together the intracellular regions of gp130 to initiate a signal transduction cascade through certain transcription factors, Janus kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs).

In addition to the membrane-bound receptor, a soluble form of IL-6R (sIL-6R) has been purified from human serum and urine. Many neuronal cells are unresponsive to stimulation by IL-6 alone, but differentiation and survival of neuronal cells can be mediated through the action of sIL-6R. The sIL-6R/IL-6 complex can stimulate neurites outgrowth and promote survival of neurons and, hence, may be important in nerve regeneration through remyelination. It may be able to inhibit microglial function. Maybe this could be tested to see if it affected progression.However would this be associated with a lot of side effects because IL-6 can do so many different things.


  1. IL-6 again....

    I am so convinced of a key role of IL-6 that I am willling to test a anti-IL-6-DMT for MS treatment. There is lots of evidence which point towards a key role in the disease process.

    I know that it has other very important roles in the body and it may have some side effects (e.g. higher risks of infections) but we already have a lot of data from RA-patients so we might come to a reasonable dosage.

    IL-6 is not the answer to WHAT causes MS but HOW to deal with it better. And if you can't get the answer to what causes something it is a good way to deal with "what to do to make it better".

    Yes it might be confirmation bias but the evidence for a key role of IL-6 is overwhelming.

    1. A note of caution in trying to extrapolate from rheumatoid arthritis to MS is that whilst anti-TNF alpha therapy can be very effective in RA, it can induce MS in some RAers. So, not all inflammation is the same.

    2. I didn't mean the anti-TNF-threapies in RA I meant the anti-IL6-therapies e.g. Tocilizumab.

      I would consider inhibiting TNF-a in MS as more on " the bad/dark side".

    3. I was just pointing out that you need to exercise caution in extrapolating from one autoimmune condition to another (that is IF MS is truly an autoimmune condition, which Prof G has his doubts on).
      There have (as I understand though I don't have the numbers) been a number of cases where people have developeed MS whilst being treated with Tocilzumab (Actenra), which may correlate with what is seen with some RA patients on anti-TNF therapy.

    4. That would be a good case of falsification (in some way). I was telling the same thing to the people at Hoffmann. IF it was a false assumption data should show that people treated with e.g. Tocilizumab would still develop MS (taking statistic distribution into consideration).

      I also don't believe in the autoimmune condition but IL-6 involvement could explain the observable autoimmune processes/reactions.

      We will see. Science is slow but in most cases comes up with the right direction. IL-6 could explain a lot of things...

    5. I agree, from what I've seen there are a few cases of neuromyelitis optica being successfully treated with tocilizumab, though whether NMO is related to MS is a matter of conjecture.

  2. I've read recently that it is thought that decreased microglia function is part of the problem in Alzheimer's. Could blocking microglia actually cause brain problems down the line because of this?

    1. The study you mention in a mouse model of Alzheimer's, found that activated microglia of an "anti-inflammatory" type (not a decrease in function), had upregulated levels of an enzyme that decreases the amount of the amino acid arginine in the brain. If they blocked this enzyme then the mice were much improved, cognitively and pathologically.

    2. MD2 since you touched on this research on arginine and the alzheimer, but would have some proximity (besides the fact that they are degenerative) in the "inflammatory" mechanism of MS with AD? Because time ago I read an article by Dr. Lawrence Steinman talking about a possible applicability of amyloid beta protein for MS in which he said: "In the Alzheimer's brain there is is very little evidence of the kind of classical neuro-inflammation you see in diseases like MS. MS doesn’t look at all like Alzheimer’s. In MS there are T cells, B cells, antibodies, macrophages. In Alzheimer’s you don’t see that.”


    3. Hi Cinara,
      In MS we have reported that there is Tau deposition in both EAE and MS tissues, though whether this is causing disease or is merely a "tombstone" marker for a dying neuron remains to be elucidated.
      Here's a link to our paper (free to view).

    4. Speaking of MS, Alzheimers, and Larry Steinman: do amiloid fragments actually ameliorate EAE? http://www.ncbi.nlm.nih.gov/pubmed/25073790

    5. Oh I understand, this interesting article that you indicated. Thank You MD2 :)))

  3. Is obesity an inflammatory disease? Does being fat over-stimulate the immune system? Is fatness and MS kind of mutual?

    1. No idea what you mean by 'fatness and MS kind of mutual'. Interestingly I've seldom met someone with MS that is 'fat' (if by this you mean grossly overweight). And I've always been at the lower end of the healthy weight range. So, if this is what you means, please elucidate further.


Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.