TY  - JOUR
AU  - Tiwari, Vini
AU  - Prajapati, Bharat
AU  - Asare, Yaw
AU  - Damkou, Alkmini
AU  - Ji, Hao
AU  - Liu, Lu
AU  - Naser, Nawraa
AU  - Gouna, Garyfallia
AU  - Leszczyńska, Katarzyna B
AU  - Mieczkowski, Jakub
AU  - Dichgans, Martin
AU  - Wang, Qing
AU  - Kawaguchi, Riki
AU  - Shi, Zechuan
AU  - Swarup, Vivek
AU  - Geschwind, Daniel H
AU  - Prinz, Marco
AU  - Gokce, Ozgun
AU  - Simons, Mikael
TI  - Innate immune training restores pro-reparative myeloid functions to promote remyelination in the aged central nervous system.
JO  - Immunity
VL  - 57
IS  - 9
SN  - 1074-7613
CY  - New York, NY
PB  - Elsevier
M1  - DZNE-2024-01122
SP  - 2173 - 2190.e8
PY  - 2024
AB  - The reduced ability of the central nervous system to regenerate with increasing age limits functional recovery following demyelinating injury. Previous work has shown that myelin debris can overwhelm the metabolic capacity of microglia, thereby impeding tissue regeneration in aging, but the underlying mechanisms are unknown. In a model of demyelination, we found that a substantial number of genes that were not effectively activated in aged myeloid cells displayed epigenetic modifications associated with restricted chromatin accessibility. Ablation of two class I histone deacetylases in microglia was sufficient to restore the capacity of aged mice to remyelinate lesioned tissue. 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. Our results provide insight into aging-associated decline in myeloid function and how this decay can be prevented by innate immune reprogramming.
KW  - Animals
KW  - Immunity, Innate
KW  - Mice
KW  - Aging: immunology
KW  - Remyelination
KW  - Microglia: immunology
KW  - Microglia: metabolism
KW  - Myeloid Cells: immunology
KW  - Myeloid Cells: metabolism
KW  - Central Nervous System: immunology
KW  - Mice, Inbred C57BL
KW  - Myelin Sheath: metabolism
KW  - Myelin Sheath: immunology
KW  - Epigenesis, Genetic
KW  - Demyelinating Diseases: immunology
KW  - Disease Models, Animal
KW  - aging (Other)
KW  - innate immunity (Other)
KW  - microglia (Other)
KW  - myelin (Other)
KW  - remyelination (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:39053462
DO  - DOI:10.1016/j.immuni.2024.07.001
UR  - https://pub.dzne.de/record/272079
ER  -