{"doi":"10.1101/2021.06.06.447262","title":"Microglial CX3CR1 <sup>I249/M280</sup> variant limits neurogenesis and remyelination in cuprizone-induced multiple sclerosis model","abstract":"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 CX3CR1 I249/M280 (h CX3CR1 I249/M280 ) variant increases MS disease progression. However, the role of h CX3CR1 I249/M280 on microglial activation and central nervous system repair and regenerative mechanisms remain unknown. Therefore, using transgenic mice expressing the h CX3CR1 I249/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 h CX3CR1 I249/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 h CX3CR1 I249/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 h CX3CR1 I249/M280 mice was associated with a significant downregulation of gene networks linked to neurogenesis following acute demyelination. Confocal microscopy showed that h CX3CR1 I249/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 h CX3CR1 I249/M280 on microglia dysfunction and therapeutic targeting of CX3CR1 to promote CNS repair in MS.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":224872,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9454,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":827110,"name":"Kaira A. Church","orcid":"0000-0002-3982-8476","position":1,"is_corresponding":false},{"id":791085,"name":"Sandra M. Cardona","orcid":"0000-0001-9128-6742","position":2,"is_corresponding":false},{"id":827420,"name":"Difernando Vanegas","orcid":null,"position":3,"is_corresponding":false},{"id":827421,"name":"Shannon A. Garcia","orcid":null,"position":4,"is_corresponding":false},{"id":333471,"name":"Wendy B. Macklin","orcid":"0000-0002-1252-0607","position":5,"is_corresponding":false},{"id":231494,"name":"Sérgio A. Lira","orcid":"0000-0002-6742-3089","position":6,"is_corresponding":false},{"id":30691,"name":"Richard M. Ransohoff","orcid":"0000-0003-0175-6910","position":7,"is_corresponding":false},{"id":269440,"name":"Erzsebet Kokovay","orcid":null,"position":8,"is_corresponding":false},{"id":797313,"name":"Chin‐Hsing Annie Lin","orcid":"0000-0002-8906-2077","position":9,"is_corresponding":false},{"id":827111,"name":"Astrid E. Cardona","orcid":"0000-0002-5093-8078","position":10,"is_corresponding":false},{"id":246268,"name":"Andrew S. Mendiola","orcid":"0000-0002-2897-3299","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-18T23:54:22.889584Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}