1. Gasdermin D activation in oligodendrocytes and microglia drives inflammatory demyelination in progressive multiple sclerosis.
- Author
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Pollock, Niall M., Fernandes, Jason P., Woodfield, Jenilee, Moussa, Eman, Hlavay, Brittyne, Branton, William G., Wuest, Melinda, Mohammadzadeh, Nazanin, Schmitt, Laura, Plemel, Jason R., Julien, Olivier, Wuest, Frank, and Power, Christopher
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CENTRAL nervous system injuries , *MULTIPLE sclerosis , *OLIGODENDROGLIA , *DEMYELINATION , *COMPLEMENT (Immunology) , *CENTRAL nervous system - Abstract
• Gasdermin D (GSDMD) activation occurs in oligodendrocytes and CNS macrophages. • GDSMD and Ninjurin 1 are induced in neuroinflammatory demyelination. • GSDMD genetic deletion reduces neuroinflammatory demyelination and axonal injury. • GSDMD activation represents a potential therapeutic target for progressive MS. Neuroinflammation coupled with demyelination and neuro-axonal damage in the central nervous system (CNS) contribute to disease advancement in progressive multiple sclerosis (P-MS). Inflammasome activation accompanied by proteolytic cleavage of gasdermin D (GSDMD) results in cellular hyperactivation and lytic death. Using multiple experimental platforms, we investigated the actions of GSDMD within the CNS and its contributions to P-MS. Brain tissues from persons with P-MS showed significantly increased expression of GSDMD, NINJ1, IL-1β, and −18 within chronic active demyelinating lesions compared to MS normal appearing white matter and nonMS (control) white matter. Conditioned media (CM) from stimulated GSDMD+/+ human macrophages caused significantly greater cytotoxicity of oligodendroglial and neuronal cells, compared to CM from GSDMD-/- macrophages. Oligodendrocytes and CNS macrophages displayed increased Gsdmd immunoreactivity in the central corpus callosum (CCC) of cuprizone (CPZ)-exposed Gsdmd+/+ mice, associated with greater demyelination and reduced oligodendrocyte precursor cell proliferation, compared to CPZ-exposed Gsdmd-/- animals. CPZ-exposed Gsdmd+/+ mice exhibited significantly increased G-ratios and reduced axonal densities in the CCC compared to CPZ-exposed Gsdmd-/- mice. Proteomic analyses revealed increased brain complement C1q proteins and hexokinases in CPZ-exposed Gsdmd-/- animals. [18F]FDG PET imaging showed increased glucose metabolism in the hippocampus and whole brain with intact neurobehavioral performance in Gsdmd-/- animals after CPZ exposure. GSDMD activation in CNS macrophages and oligodendrocytes contributes to inflammatory demyelination and neuroaxonal injury, offering mechanistic and potential therapeutic insights into P-MS pathogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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