Block microglia may not always be good

B

Brutons tyrosine kinase inhibitors are being trialed in progressive MS. What will happen? BTK is not only expressed by B cells but it is also expressed my macrophages. Angy microglia have been considered to be the bad guys in progressive MS, yet they can be the good guys too and you have to remove the myelin debris to get repair. So blocking them could be a good or bad thing. It is going to be a balance that determines the outcome.

Another approach to getting rid of microglai is to inhibit CSF-1. In the study in mice they evaluated the effects of a reduction in microglial activation through orally administered brain-penetrant colony-stimulating factor-1 receptor (CSF-1R) inhibitor BLZ945 (BLZ) on neurodegeneration and its correlation with demyelination, astroglial activation and behavior in a chronic CPZ-induced demyelination model. It was reported that BLZ treatment successfully reduced the microglial population and myelin loss, however axonal degeneration was more prominent upon BLZ treatment. So what will happen with the BTK inhibitors?

Wies Mancini VSB, Di Pietro AA, de Olmos S, Silva PR, Vence M, Marder M, Igaz LM, Marcora MS, Pasquini JM, Correale JD, Pasquini LA. Colony-stimulating factor-1 receptor inhibition attenuates microgliosis and myelin loss but exacerbates neurodegeneration in the chronic cuprizone model. J Neurochem. 2021 Dec 22. doi: 10.1111/jnc.15566.

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  • Sir, what the findings were when the mouse models were treated with BTKI itself. Did it too cause axonal degeneration? Thanks and regards. 🙏

    • Did it cause axonal degeneration, I dont think so but the experiments were done for that long on the stuff I have seen

  • When is it looking like we will get some solid answers to BTKi effectiveness?

    2023?

    And if BTKi don’t produce positive results in progressive MS. Is it back to the drawing board or will a BTKi failure help shed more light on the progressive side of MS

    Going back to the brain drain issue, macrophages are just doing their jobs, what else will build up in the brain if macrophages are inhibited……

  • Yep

    “Therapeutic targeting of glia in CNS disease is a balancing act since these cells also exert neuroprotective and neuroplastic effects, depending on the phase of recovery from CNS injury or stage of neurodegenerative disease,” King and Nabors said

    https://medicalxpress.com/news/2021-09-small-molecule-potently-attenuates-neuroinflammation.html

    Not all microglia are made equall

    this study unveils the presence of a myeloid cell subtype originating from the SVZ and associated WM areas with increased CSF1Ri resistance that yields a dynamic wave of repopulating cells to reconstitute the microglial-depleted brain. These cells exhibit distinct properties compared to homeostatic microglia, sharing similar phenotypic and transcriptional profiles to DAMs and WAMs. Together, these results not only highlight the complexity and diversity of myeloid cells in the adult brain, but establish a model system that provides new insight on myeloid cell homeostasis and dynamics in the brain.

    https://elifesciences.org/articles/66738?utm_source=content_alert&utm_medium=email&utm_content=fulltext&utm_campaign=13-September-21-elife-alert

    Microglia are another kind of brain cell. They have long been considered the bad guys of brains, because they always show up near injuries and inflammation. However, Nishiyama and Sherafat found that microglia located next to OPCs in the brain regions that are rich in nerve bundles will stick a particular protein on their cell membrane when the nerves are developing or damaged. The protein sticks out and actually touches nearby OPCs. When the protein touches a growth factor receptor on an OPC, the OPC starts to multiply and produce more mature versions of itself that make or repair the insulation. That seems to be one way, at least, that OPCs are activated.

    https://medicalxpress.com/news/2021-05-nerves-requires-prods-protein.html

    I have paper upon papers saying that microglia are the bad guys but also they are the good guys

    Nice post

  • If you were MS patient currently on CD20, would you move onto a BTKi if trials show improvements for progressive MS?

    • Good question….BTKi will have the vaccine issues of anti-CD20 this has already been seen in cancer….as for the progression element this may encourage switching but it has to be said the relapse inhibition data did not seem as good but the comparisons are not head to head….again I suspect the trials are started too late…lets see

      • I’ve been round in circles for 10 years about microglia, B- & T-cells, membrane phospholipid chem, and membrane Ca2+ pumps in re protein folding.
        My EDS/MS crossover interests lead me to believe the pattern of progressive damage and and various ‘functional’ disorders is remarkably similar in both allegedly discrete conditions. I’ve mostly been thinking about why there is such a high rate of EDS/MS comorbidity.
        Maybe the upcoming viral research explosion will shed some light.
        PS: really like the way you use the word ‘neuroprotective’- maybe more of us should (if the Brit expression makes sense there) just call a spade a bloody great shovel.

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