To deplete or Not to Deplete.That is the Question? Microglia are the good Guys?

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Microglia suppress the secondary progression of autoimmune encephalomyelitis.Tanabe S, Saitoh S, Miyajima H, Itokazu T, Yamashita T. Glia. 2019 May 20. doi: 10.1002/glia.23640. [Epub]

So all you will remember here is microglia inhibit secondary progression. They are the good guys. Which is funny because we have been saying they are the bad guys.

They report Microglia depletion exacerbated the secondary progression of autoimmune encephalomyelitis. 

• Microglia deletion promoted inflammation, demyelination, and axonal degeneration by increasing the proliferating CD4+ T cells and reducing Treg cells.

Tanaebe et al. 2019

Microglia are immune cells that localize in the CNS and play important roles in MS pathology. There are papers saying that it can inhibit the development of EAE. There are suggestions that minocyline that can inhibit microglia inhibit EAE and MS. So in this study they use an agent that blocks colony-stimulating factor-1 receptor, which inhibits microglia.

They used a compound called PLX-3397 (pexidartinib to inhibit CSF-1 effects). It is a  tyrosine kinase inhibitor of the colony stimulating factor-1 receptor and other tyrosine kinases (Kit and Flt3), used to grow bloood-based stem cells and is involved in the generation of macrophages. This is been used in inflammatory joint disease and some cancers. It depletes microglia from the brain it also depletes macrophages outside of the brain.

CSF-1 makes microglia grow

Increased expression of colony-stimulating factor-1 in mouse spinal cord with experimental autoimmune encephalomyelitis correlates with microglial activation and neuronal loss. Gushchina S, Pryce G, Yip PK, Wu D, Pallier P, Giovannoni G, Baker D, Bo X. Glia. 2018;66:2108-2125.

We would have blocked this in EAE by now had we not had to wait essentially a Year for the Home Office Inspectorate to approve doing the experiment, after a year of doing the ethics and Home office application (Some of the slowness here was my fault)…no wonder animal experimentation gets moved outside the UK, as it is too slow to be responsive.

Based on published data, this approach should have inhibited EAE as it has been done by Genzyme (reported at ECTRIMS) and other people using another related drug PLX5622 (CSF-1R inhibitor)

Csf1R inhibition attenuates experimental autoimmune encephalomyelitis and promotes recovery. Nissen JC, Thompson KK, West BL, Tsirka SE. Exp Neurol. 2018;307:24-36

Nissen et al. 2018

In the Nissen et al 2018 paper they not only show that CSF-1R inhibition reduces EAE and they report that oligodendrocytes increase. More myelin=more target for anti-myelin T cells, but the C57BL/6 mouse doesn’t really relapse. However NOD mouse can relapse. Is this a problem.

So what happened here (Tanabe et al. 2019). If NOD mice were fed drug after their first episode they ended up with worse disease. The controls didn’t get permanently paralysed but looking at the line graph did not recover after their relapse. Their relapse occurred around day 30-40….saying that the initial worsening was due to relapse not insidious progression from the first attack as implied so it it is not secondary progressive when treatment starts but relapsing remitting.

The severity of the relapse was worse and it had more T cells and more macrophages. By day 40-45 in the treated group they are hindlimb paralysed as a consequence of the relapse and their front legs have gone, by about day 55 their front and back legs were paralysed and you are getting worse and dying (At what point do you say stop!..These animals have suffered enough!. We could not repeat this as our ethics will not let us do this).

Tanabe et al. 2019

They looked in the spinal cord at day 30 and there were loads of cells in the spinal cord loads more inflammatory cells in the treated animals, so they had a worse relapse (more blood brain barrier breakdown) and took on more damage and so recovered less.

This would trigger more apparent real secondary progression but the problem here is probably with the relapse. But the relapse has damaged the nerves and it takes a little time for them to be destroyed. However, there were no microglia there, suggesting that the worsening wasn’t microglial related. But that has already been suggested.

Microglia Are Irrelevant for Neuronal Degeneration and Axon Regeneration after acute Injury. Hilla AM, Diekmann H, Fischer D. J Neurosci. 2017 Jun 21;37(25):6113-6124.

So maybe we say “Should we care about the microglia and forget about minocyline”, which is also supposed to inhibit microglia.

Were the microglia removed apparently this happens in about a week, but the relapses had occurred by then, is that why there is no inhibition? The microglia are bad guys as they help attacks and are then good guys because they clear the debris away for repair. This has been shown in other systems. What is the reality?

The problem is this model is not really secondary progressive in the way it is being used (watch this space). The end result here, is surely no-one is going to go near this approach in MS as it now becomes very risky.

Avenue to Treatment Closed.

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3 comments

Leave a Reply to luis fernando Cancel reply

  • Is it just me or is the title of the lead paper the complete opposite of the paper’s results? What am I not understanding (a great deal it appears).

  • Controversial subject

    One of the “Grande cromo” ms research Bruce trapp

    Said that

    “Microglia are in the brain to protect it and they
    do so through several mechanisms. Phagocytic removal
    of debris is fundamental to slowing the progression of
    MS and other neurodegenerative diseases. Many brains
    in our MS autopsy cohort have lost over 30% of their
    volume and include significant cortical thinning.
    Amazingly, little cellular debris can be detected in these
    brains, which is indicative of the efficiency of microglia
    in removing cellular debris. Inhibition of microglial
    activation and suppression of debris removal would
    accelerate, not ameliorate, disease progression.

    Much, if not all, of the cortical damage in MS
    can be attributed to the microglial cell – No

    DOI: 10.1177/
    1352458517743094

    Others have said:

    The present study describes the histopathological changes
    found in autopsies of multiple sclerosis patients who had
    received ASCT. Histopathological and immunocytochemical
    examinations revealed a marked suppression of inflammatory
    activity with very few T cells and no B cells or plasma
    cells within the lesions, either parenchymally or perivascularly.
    However, we found signs of ongoing active demyelination
    as well as evidence for recent acute axonal damage
    in areas of macrophage/microglial activation.

    This is also interesting :
    Surprisingly, we found no B cells, plasma cells or
    lymphoid follicle-like structures in our cases, although it is
    suggested that pretransplant plasma cells and, accordingly,
    possible pathogenetic antibodies persist in the CNS after
    extremely lymphoablative conditioning (Storek et al., 2004).
    Thus, the pathogenic role of plasma cells or antibodymediated
    damage remains uncertain.

    Autologous haematopoietic stem cell transplantation
    fails to stop demyelination and neurodegeneration in
    multiple sclerosis

    Brain (2007), 130, 1254^1262

    Again they are bad guys

    Conclusions: Microglia/macrophages expressing C5aR are increased at the GML edge. Complement activation and the generation of pro-inflammatory anaphylatoxins such as C5a, may drive a neurotoxic microglial reaction, which will contribute to cortical pathology in progressive MS.

    https://onlinelibrary.ectrims-congress.eu/ectrims/2018/ectrims-2018/228897/rhian.evans.complement.receptor-positive.microglia.at.the.expanding.grey.html?f=media=3*search=Complement%20receptor-positive%20microglia%20at%20the%20expanding%20grey%20matter%20lesion%20edge*listing=3*browseby=8

    And bad guys again

    Increased DGM microglial activation can be detected in patients with MS and is associated with
    regional atrophy and physical disability.

    http://indexsmart.mirasmart.com/AAN2019/PDFfiles/AAN2019-002321.pdf

    Ps: Grande cromo=maven

    🙂

    obrigado

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