Defective fractalkine‐CX3CR1 signaling aggravates neuroinflammation and affects recovery from cuprizone‐induced demyelination. Issue 5 (12th May 2022)

• Record Type: Journal Article
• Authors: Mendiola, Andrew S.; Church, Kaira A.; Cardona, Sandra M.; Vanegas, Difernando; Garcia, Shannon A.; Macklin, Wendy; Lira, Sergio A.; Ransohoff, Richard M.; Kokovay, Erzsebet; Lin, Chin‐Hsing Annie; Cardona, Astrid E.
• Is Part Of: Journal of neurochemistry. Volume 162:Issue 5(2022)
• Page Start: 430
• Page End: 443
• Publication Date: 2022-05-12
• Subjects: cuprizone -- CX3CR1 -- Fractalkine -- microglia -- multiple sclerosis -- myelination; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15616
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Microglia have been implicated in multiple sclerosis (MS) pathogenesis. The fractalkine receptor CX3CR1 limits the activation of pathogenic microglia and the human polymorphic CX3CR1 I249/M280 (h CX3CR1 I249/M280 ) variant increases disease progression in models of MS. However, the role of h CX3CR1 I249/M280 variant on microglial activation and central nervous system repair mechanisms remains unknown. Therefore, using transgenic mice expressing the h CX3CR1 I249/M280 variant, we aimed to determine the contribution of defective CX3CR1 signaling to neuroinflammation and remyelination in the cuprizone model of focal demyelination. Here, we report that mice expressing h CX3CR1 I249/M280 exhibit marked demyelination and microgliosis following acute cuprizone treatment. Nanostring gene expression analysis in demyelinated lesions showed that h CX3CR1 I249/M280 but not CX3CR1‐deficient mice up‐regulated the cuprizone‐induced gene profile linked to inflammatory, oxidative stress, and phagocytic pathways. Although CX3CR1‐deficient (CX3CR1‐KO) and fractalkine‐deficient (FKN‐KO) mice displayed a comparable demyelination and microglial activation phenotype to hCX3CR1 I249/M280 mice, only CX3CR1‐deficient and CX3CR1‐WT mice showed significant myelin recovery 1 week from cuprizone withdrawal. Confocal microscopy showed that h CX3CR1 I249/M280 variant inhibits the generation of cells involved in myelin repair. Our results show that defective fractalkine signaling contributes to regional differences in demyelination, and suggest that the CX3CR1 pathway activity may be a key mechanism for limiting toxic gene responses in neuroinflammation. Cover Image for this issue: https://doi.org/10.1111/jnc.15416 Abstract : In this study, we investigated the contribution of defective fractalkine (FKN)‐CX3CR1 signaling to neuroinflammation and remyelination in the cuprizone model of focal demyelination. Histological analysis showed that mice with defective FKN‐CX3CR1 signaling exhibit marked demyelination and microglial activation in the corpus callosum following acute cuprizone treatment. We utilized a mouse strain expressing the human CX3CR1I249/M280 variant (hCX3CR1I249/M280), which showed an exacerbated demyelination and proinflammatory gene expression profile in lesions compared to both CX3CR1‐WT and ‐KO cuprizone‐treated mice. Our study showed that defective FKN‐CX3CR1 signaling delayed remyelination and the presence of mature oligodendrocytes in lesions following recovery from cuprizone treatment. Cover Image for this issue: https://doi.org/10.1111/jnc.15416