Innate immune training restores pro-reparative myeloid functions for remyelination in aged central nervous system

Tiwari, Vini (2024): Innate immune training restores pro-reparative myeloid functions for remyelination in aged central nervous system. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)

Abstract

The age-related decline in the nervous system's capacity to regenerate impairs functional recovery after demyelinating injury. When damage or inflammation occurs in the brain, microglia are the first line of defense. Recovery from demyelinating injury is hindered by age-related changes in the phenotype of microglia. There is evidence that microglial metabolic capacity is overwhelmed by myelin debris in the aged subjects, preventing tissue regeneration, but the mechanisms underlying this effect are not well understood. Many genes that are inefficiently activated in aged microglia/macrophages in a model of demyelination were found to have epigenetic modifications associated with decreased chromatin accessibility. The ability of aged mice to re-myelinate damaged tissue was restored by selectively deleting two class I histone deacetylases in microglia/macrophages. We used Bacillus Calmette-Guerin (BCG), a live-attenuated vaccine, to train the innate immune system, and detected epigenetic reprogramming of brain-resident myeloid cells and functional restoration of myelin debris clearance and lesion recovery. Further, trained microglia showed enhanced activation and improved myelin lipid metabolism in response to demyelinating injury, a process mediated at least in part by histone deacetylases. Our results provide insight into aging-associated decline in myeloid function and how this decay can be prevented by innate immune system reprogramming. In conclusion, we demonstrate that epigenetically mediated innate immune training of microglia can serve as strategy to convert microglia into pro-reparative state following demyelinating injury.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Microglia, Remyelination, Innate immunity, Epigenetics
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Graduate School of Systemic Neurosciences (GSN)
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 8. Februar 2024
• 1. Bericht­erstatter:in: Simons, Mikael