Tuesday, 23 July 2013

M2 Good macrophages support remyelination


The lack of therapies for progressive multiple sclerosis highlights the need to understand the regenerative process of remyelination that can follow CNS demyelination. This involves an innate immune response consisting of microglia and macrophages, which can be polarized to distinct functional phenotypes: pro-inflammatory (M1) and anti-inflammatory or immunoregulatory (M2). We found that a switch from an M1- to an M2-dominant response occurred in microglia and peripherally derived macrophages as remyelination started. Oligodendrocyte differentiation was enhanced in vitro with M2 cell conditioned media and impaired in vivo following intra-lesional M2 cell depletion. M2 cell densities were increased in lesions of aged mice in which remyelination was enhanced by parabiotic coupling to a younger mouse and in multiple sclerosis lesions that normally show remyelination. Blocking M2 cell-derived activin-A inhibited oligodendrocyte differentiation during remyelination in cerebellar slice cultures. Thus, our results indicate that M2 cell polarization is essential for efficient remyelination and identify activin-A as a therapeutic target for CNS regeneration.

Prof Franklinstein and fffffffffrench-constant are back on the trail of myelin repair. They showed that to get effective remyelination you first have to clear up the myelin debris. The macrophages have been split into M1 and M2 cells. The M1 cells are the bad guys who cause damage and the M2 are more regulatory. So with inflammation you want to start with the M1 to get rid of an infections and then use an M2 to mop up and repair the damage. This what is found here and it is the M2 macrophages that are promoting repair. These cells produce factors that allow oligodendrocytes to mature to produce myelin. They identify activin-A as important in this

Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Activin- A has loads of different activities and again may be an achilles heel to the approach as any drug targeting this pathway will have the potential of loads of side effects, but there is only one way to find out.



6 comments:

  1. Re remyelination, would a analogy be like putting the insulation sheathing back over bared copper inner cable?
    The inner cable being the one which does all the work and the outer for prtection, so if the inner cable is split no matter how much insulation gets wrapped round, the signal will not get through ?

    Are people looking at repairing axons ? or does this all fit in the same research?
    Am I missing something? Is it possible to have an edss of 7.5 and still have little axon damage ?

    Regards as always.

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    Replies
    1. http://brain.oxfordjournals.org/content/125/10/2202

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    2. http://www.ncbi.nlm.nih.gov/pubmed/21441916

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    3. Can you put some meat on the bones MD & MD2 .Thanks.
      Regards as always.

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    4. That analogy is spot on. We're looking at protecting the axons from dying rather than repair, once the death cascade is in full swing it's very diffficult to reverse it.With an EDSS of 7.5 there would have to be significant axonal loss.

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  2. Still think parabiotic coupling mice is horrendously unethical.

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