Die Rolle der oligodendrogliären Differenzierungsinhibitoren p57kip2 und GPR17 in der Pathologie der Multiplen Sklerose
Molekulare Biologie und Physiologie von Nerven- und Gliazellen
Zusammenfassung der Projektergebnisse
In this research fellowship the envelope protein (ENV) of the human endogenous retrovirus type W (HERV-W) which the fellowship holder had previously found to interfere with oligodendroglial precursor cell (OPC) differentiation was more closely studied with regard to its trafficking mechanisms in the MS brain. OPC differentiation into mature myelin-forming oligodendrocytes is vital for remyelination of demyelinated axons and thus MS lesion repair. The detrimental effect of ENV on OPCs was found to be caused by an upregulation of proinflammatory genes - above all, of inducible nitric oxide synthase (iNOS). Here, the fellowship holder could identify so-called microglial cells as highly relevant players in ENV trafficking in the MS brain. These cells are part of the healthy brain’s innate immune system as a first line of defense against pathological agents but can also produce proinflammatory cytokines in the MS brain. Thereby they fuel the ongoing inflammatory process by cytokine-mediated activation of other immune cells ultimately leading to myelin destruction. The fellowship holder’s study now revealed that In MS lesions ENV is present in a subpopulation of microglial cells, in cells within perivascular cuffs and in the extracellular space in the parenchyma. Furthermore, it could be shown that ENV-positive microglia express ENV receptor Toll-like receptor 4 (TLR4) – a prerequisite for functional relevance - and that they are in direct contact with axons, wrap around them and can be found adjacent to bulb- and transection-like axonal structures indicative of axonal injury. Lastly, the fellowship holder could demonstrate that ENV-positive microglia phagocytose PLP debris in MS lesions. In summaryand in light of the fellowhip holder’s previous studies demonstrating a strong proinflammatory effect of the ENV protein on CNS cells the observations made in this project suggest that ENV-MSRV might play an important role in the context of proinflammatory microglial acitvation in MS. It is conceivable that microglia that either express ENV endogenously as a result of MSRV activation or have phagocytosed parenchymal ENV undergo a proinflammatory activation via the TLR4 signaling cascade. These cells might then initiate an attack on remaining myelin sheaths and could contribute to myelin and axonal damage ultimately leading to axonal degeneration – a hypothesis supported byan ongoing follow-up studyin the fellowship holder’s home laboratory showing that stimulation with recombinant ENV leads to a strong induction of proinflammatory M1-type genes such as TNFα and iNOS in rodent microglia.
Projektbezogene Publikationen (Auswahl)
- Promoting remyelination in Multiple Sclerosis: Current drugs and future prospects. Mult Scler. 2015 Apr;21(5):541-549. Epub 2015 Jan 26
Kremer D., Küry P., Dutta R.
(Siehe online unter https://doi.org/10.1177/1352458514566419)
