This is a post from the Repair lab in Cambridge about repair. It.is free.to view so have a read…you have paid for that pleasure.
de Faria O Jr, Vagionitis S, Lopez-Lopez A, Perry M, Wong JJY, Rodríguez-Kirby L, Hervé B, Varga BV, Agirre E, Ghosh S, Timmler S, Yucel M, Setley AT, Evans KA, Birgisdóttir TM, Gíslason S, Ng YT, Kremler C, Gautier HOB, Kamen Y, Pivonkova H, Volbracht K, Hildebrand F, Cepeda CA, Rueda-Carrasco J, Hong S, Malliaras G, Dietmann S, Castelo-Branco G, Káradóttir RT. Focal white matter lesions drive grey matter inflammation and synapse loss. Nature. 2026 Apr 22. doi: 10.1038/s41586-026-10414-w. Epub ahead of print. PMID: 42020752.
Focal white matter lesions occur in most neurodegenerative disorders. Despite occurring early in disease, white matter lesions are considered to be independent of, or secondary to, grey matter neuroinflammation, synapse loss and altered neuronal activity Notably, their functional effect on neuronal circuits remains understudied. (Tell this to the MRIers) To address this, we generated a focal white matter lesion in the rat brain within a clinically relevant, anatomically well-defined circuit, in which these lesions occur in many neurodegenerative disorders. Here we show that focal white matter lesions evoke transient neuronal activity changes and microgliosis, with subsequent synapse loss and increased microglial engulfment in the grey matter, which is reversed if myelin regeneration completes. Grey matter microgliosis is often considered to be detrimental; however, we show that it is an integral part of regeneration and is conserved across three distinct mouse circuits and lesioning methods. Preventing these transient changes in the grey matter blocks myelin regeneration in the white matter. Conversely, inducing myelin regeneration failure leads to chronic grey matter neuroinflammation. This recapitulates the low-grade inflammation considered to be a dominant mechanism underlying neurodegeneration. Our findings reveal a form of regenerative plasticity coupling white matter integrity to grey matter function, which may underlie multiple neurodegenerative conditions, and highlight the potential of targeting myelin regeneration to prevent chronic neuroinflammation.
Now I typically choose not to make comment on such papers and this post is not really about the paper. Perhaps disturbingly they say that consensus suggests that grey matter damage is independent of white matter damage and show that it is not. However in MS, many grey matter lesions border white matter lesions You also have to realise that white matter in the spinal cord could impact on the brain grey matter etc. But another bit of dogma is that microglial activity is universally bad. This study shows that with molecular tools it.can show that the two good and bad microglia view is too simplistic. The cell activity is not static and changes with context.
This is yet another example to show that inflammation can be good and bad. Inflammation serves to limit damage from infection or perhaps autoimmunity and then repairs the battle ground. I have known this concept since I was an academic amoeba and so it is perhaps, nothing new. However it reiterates that there is perhaps good and.bad inflammation in diseases like multiple sclerosis and this inflammation can involve macrophages and microglia…which have been often viewed as the bad boys and girls…However you can’t repair until you have cleared up the crap… You don’t.build.a new house after the old house fell down without clearing the building site. This was shown by Cambridge Researchers decades ago…
It is funny that we often do not really think about this properly. Brutons trysosine kinase inhibitors block macrophage function and so the question is does it block good inflammation or bad inflammation. How many times in reviews is this element totally ignored.
I have seen suggestions from mice that it only blocks bad inflammation but I am not sure I buy this. This is because if you look at good and bad inflammatory cells they both express BTK and perhaps the good inflammatory cells express more so the impact will be a balance, as it so often is. There are good and bad T cells and good and bad B cells it is context dependent.
COI None
Source: multiple-sclerosis-research.org