Microglial CX3CR1I249/M280 variant limits neurogenesis and remyelination in cuprizone-induced multiple sclerosis model

Mendiola, A. S.; Church, K. A.; Cardona, S. M.; Vanegas, D.; Garcia, S. A.; Macklin, W.; Lira, S. A.; Ransohoff, R. M.; Kokovay, E.; Lin, C.-H. A.; Cardona, A. E.

doi:10.1101/2021.06.06.447262

bioRxiv · 10.1101/2021.06.06.447262

Microglial CX3CR1I249/M280 variant limits neurogenesis and remyelination in cuprizone-induced multiple sclerosis model

Mendiola, A. S.·Church, K. A.·Cardona, S. M.·Vanegas, D.·Garcia, S. A.·Macklin, W.·Lira, S. A.·Ransohoff, R. M.·Kokovay, E.·Lin, C.-H. A.·Cardona, A. E.

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Abstract

Microglia have been implicated in multiple sclerosis (MS) pathogenesis. The fractalkine receptor CX3CR1 regulates the activation of pathogenic microglia in models of MS and the human polymorphic CX3CR1I249/M280 (hCX3CR1I249/M280) variant increases MS disease progression. However, the role of hCX3CR1I249/M280 on microglial activation and central nervous system repair and regenerative mechanisms remain unknown. Therefore, using transgenic mice expressing the hCX3CR1I249/M280 variant, we aimed to determine the contribution of defective CX3CR1 signaling to remyelination and neurogenesis in the cuprizone model of focal demyelination. Here, we report that mice expressing hCX3CR1I249/M280 exhibit marked demyelination and microgliosis follow acute cuprizone treatment. Cuprizone-treated CX3CR1-deficient and fractalkine-deficient mice displayed a comparable phenotype. Nanostring gene expression analysis in demyelinated lesions showed that hCX3CR1I249/M280 upregulates genes associated with inflammation, oxidative stress and disease-associated microglia. In addition, gene expression analysis in the subgranular zone (SGZ) of the hippocampus in hCX3CR1I249/M280 mice was associated with a significant downregulation of gene networks linked to neurogenesis following acute demyelination. Confocal microscopy showed that hCX3CR1I249/M280 or loss of CX3CR1 signaling inhibits the generation of progeny from the neurogenic niche, including cells involved in myelin repair. These results provide evidence for the pathogenic capacity of hCX3CR1I249/M280 on microglia dysfunction and therapeutic targeting of CX3CR1 to promote CNS repair in MS.

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Mendiola, A. S., Church, K. A., Cardona, S. M., Vanegas, D., Garcia, S. A., Macklin, W., Lira, S. A., Ransohoff, R. M., Kokovay, E., Lin, C.-H. A., Cardona, A. E.. 2021-06-07. Microglial CX3CR1I249/M280 variant limits neurogenesis and remyelination in cuprizone-induced multiple sclerosis model. https://doi.org/10.1101/2021.06.06.447262

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