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

Andrew S. Mendiola, Kaira A. Church, Sandra M. Cardona, Difernando Vanegas, Shannon A. Garcia, Wendy Macklin, Sergio A. Lira, Richard M. Ransohoff, Erzsebet Kokovay, Chin-Hsing Annie Lin, Astrid E. Cardona
doi: https://doi.org/10.1101/2021.06.06.447262
Andrew S. Mendiola
1Gladstone Institutes, San Francisco, California, 94158, USA
2Department of Biology, The University of Texas at San Antonio, San Antonio, TX 78249, USA
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  • For correspondence: andrew.mendiola@gladstone.ucsf.edu
Kaira A. Church
2Department of Biology, The University of Texas at San Antonio, San Antonio, TX 78249, USA
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Sandra M. Cardona
2Department of Biology, The University of Texas at San Antonio, San Antonio, TX 78249, USA
3South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, USA
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Difernando Vanegas
2Department of Biology, The University of Texas at San Antonio, San Antonio, TX 78249, USA
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Shannon A. Garcia
2Department of Biology, The University of Texas at San Antonio, San Antonio, TX 78249, USA
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Wendy Macklin
4Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, CO 80045, USA
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Sergio A. Lira
5Precision Immunology Institute Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Richard M. Ransohoff
6Third Rock Ventures, Boston, MA 02116, USA
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Erzsebet Kokovay
7Cell Systems and Anatomy, UT-Health Science Center San Antonio, San Antonio TX 78229, USA
8Barshop Institute of Longevity and Aging Studies, San Antonio, TX 78245, USA
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Chin-Hsing Annie Lin
2Department of Biology, The University of Texas at San Antonio, San Antonio, TX 78249, USA
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Astrid E. Cardona
2Department of Biology, The University of Texas at San Antonio, San Antonio, TX 78249, USA
3South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX 78249, USA
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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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* Co-first Authorship

  • 1 present address

  • Email: astrid.cardona{at}utsa.edu

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 07, 2021.
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Microglial CX3CR1I249/M280 variant limits neurogenesis and remyelination in cuprizone-induced multiple sclerosis model
Andrew S. Mendiola, Kaira A. Church, Sandra M. Cardona, Difernando Vanegas, Shannon A. Garcia, Wendy Macklin, Sergio A. Lira, Richard M. Ransohoff, Erzsebet Kokovay, Chin-Hsing Annie Lin, Astrid E. Cardona
bioRxiv 2021.06.06.447262; doi: https://doi.org/10.1101/2021.06.06.447262
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Microglial CX3CR1I249/M280 variant limits neurogenesis and remyelination in cuprizone-induced multiple sclerosis model
Andrew S. Mendiola, Kaira A. Church, Sandra M. Cardona, Difernando Vanegas, Shannon A. Garcia, Wendy Macklin, Sergio A. Lira, Richard M. Ransohoff, Erzsebet Kokovay, Chin-Hsing Annie Lin, Astrid E. Cardona
bioRxiv 2021.06.06.447262; doi: https://doi.org/10.1101/2021.06.06.447262

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