This is a summary of V. Tiwari et al. (2024). Innate immune training restores pro-reparative myeloid functions to promote remyelination in the aged central nervous system as published in Immunity. https://doi.org/10.1016/j.immuni.2024.07.001
The challenge
Loss of myelin is typically associated with diseases where the immune system mistakenly attacks the myelin, as seen in multiple sclerosis (MS). The good news is that lost myelin can be regenerated (remyelination). However, the capacity to remyelinate MS lesions declines significantly with age. Previous research has demonstrated that an excess of myelin debris can hinder the ability of microglia to support tissue regeneration in aging. However, the specific mechanisms causing this are not well understood. Our study, therefore, aimed to investigate whether age-related changes in epigenetics play a role in reducing the responsiveness and reparative functions of microglia in demyelinating lesions. We also explored the possibility of using innate immune training to epigenetically reprogram and invigorate microglial responses, with the goal of reinstating reparative inflammation.
Our approach
We used mouse models to model and study the demyelination process. Furthermore, we used Bacillus Calmette-Guerin (BCG), a live-attenuated vaccine strain of Mycobacterium bovis, to train the innate immune system in a mouse model.
Our findings
Our mouse model showed that a substantial number of genes were not effectively activated in aged myeloid cells and that these genes displayed epigenetic modifications that are associated with restricted chromatin accessibility. We showed that epigenetic alterations, in particular histone acetylation levels, contribute to the poor responsiveness of microglia and, therefore, limit the responses in case of injury. Subsequently, removal of two class I histone deacetylases (HDAC1 and HDCA2) – which reversibly regulate the acetylation status of histones – in microglia restored the aged mice's ability to remyelinate damaged tissue. Furthermore, after training the immune system, we observed epigenetic reprogramming of brain-resident myeloid cells and functional restoration of myelin debris clearance and lesion recovery.
The implications
Our results suggest that aging leads to loss of microglial plasticity, causing the microglia to lose their capacity to mount a finely tuned response to injury. Our research implies that immune training may provide strategy for future therapeutic avenues.
Creating SyNergies
The research was led by Mikael Simons und included SyNergy members Martin Dichgans and Ozgun Gokce.
