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.
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
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).
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.