ArticleJournal of neuroinflammation2021
Citrullinated myelin induces microglial TNFα and inhibits endogenous repair in the cuprizone model of demyelination.
Article in Journal of neuroinflammation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- NEMO (IKKγ) citrullination in microglia promotes neuroinflammation in the post-ischemic brain.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Neural Stem Cells in Multiple Sclerosis: A Comprehensive Review of Preclinical and Clinical Evidence for CNS Repair and Translational Hurdles.Applied biochemistry and biotechnology · 2026Review
- Myelin Basic Protein Post-Translational Modifications Orchestrate Astrocyte Regulatory Networks.NeuroSci · 2026Article
- Microglial handling of myelin debris and remyelination after ischaemic stroke: recognition, intracellular processing, lipid fate, and oligodendroglial repair.Frontiers in cellular neuroscience · 2026Review
- Dynamic Transcriptomic and Cellular Remodeling Underlie Cuprizone-Induced Demyelination and Endogenous Repair in the CNS.Antioxidants (Basel, Switzerland) · 2025Article
- Arginine metabolism in myeloid cells in health and disease.Seminars in immunopathology · 2025Review
- MRS3997, a dual adenosine ANeuropharmacology · 2025Article
- Micro-diffusely abnormal white matter: An early multiple sclerosis lesion phase with intensified myelin blistering.Annals of clinical and translational neurology · 2024Article
- Multiple Sclerosis: New Insights into Molecular Pathogenesis and Novel Platforms for Disease Treatment.Current drug research reviews · 2024Review
- Cytotoxic CNS-associated T cells drive axon degeneration by targeting perturbed oligodendrocytes iniScience · 2023Article
- Microglia/macrophages require vitamin D signaling to restrain neuroinflammation and brain injury in a murine ischemic stroke model.Journal of neuroinflammation · 2023Article
- Remyelination in Multiple Sclerosis: Findings in the Cuprizone Model.International journal of molecular sciences · 2022Review
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3 authors.
Funding
Abstract
backgroundMicroglia are the primary phagocytes of the central nervous system and are responsible for removing damaged myelin following demyelination. Previous investigations exploring the consequences of myelin phagocytosis on microglial activation overlooked the biochemical modifications present on myelin debris. Such modifications, including citrullination, are increased within the inflammatory environment of multiple sclerosis lesions.
methodsMouse cortical myelin isolated by ultracentrifugation was citrullinated ex vivo by incubation with the calcium-dependent peptidyl arginine deiminase PAD2. Demyelination was induced by 6 weeks of cuprizone (0.3%) treatment and spontaneous repair was initiated by reversion to normal chow. Citrullinated or unmodified myelin was injected into the primary motor cortex above the cingulum bundle at the time of reversion to normal chow and the consequent impact on remyelination was assessed by measuring the surface area of myelin basic protein-positive fibers in the cortex 3 weeks later. Microglial responses to myelin were characterized by measuring cytokine release, assessing flow cytometric markers of microglial activation, and RNAseq profiling of transcriptional changes.
resultsCitrullinated myelin induced a unique microglial response marked by increased tumor necrosis factor α (TNFα) production both in vitro and in vivo. This response was not induced by unmodified myelin. Injection of citrullinated myelin but not unmodified myelin into the cortex of cuprizone-demyelinated mice significantly inhibited spontaneous remyelination. Antibody-mediated neutralization of TNFα blocked this effect and restored remyelination to normal levels.
conclusionsThese findings highlight the role of post-translation modifications such as citrullination in the determination of microglial activation in response to myelin during demyelination. The inhibition of endogenous repair induced by citrullinated myelin and the reversal of this effect by neutralization of TNFα may have implications for therapeutic approaches to patients with inflammatory demyelinating disorders.
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