Recently, researchers from the Technical University of Munich in Germany published a research paper titled "Innate immune training restores pro-reparative myeloid functions to promote remyelination in the aged central nervous system" in the Cell journal Immunity. The study showed that age-related epigenomic changes impair the regenerative function of microglia, but innate immune training can reverse these changes and enhance their pro-regenerative ability in demyelinating injuries. These findings provide new insights into the aging-related decline of myeloid function and how to prevent this decline through innate immune reprogramming.
Figure 1. The innate immune training response is abolished in microglia depleted of HDAC1/2. (Tiwari V, et al., 2024)
Following primary demyelination in diseases such as multiple sclerosis (MS), a spontaneous regenerative process called remyelination is initiated, resulting in the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes, which generate new myelin sheaths around axons. The repair process requires an injury-induced innate response that is tuned to the damaged tissue to promote its clearance from the lesion area. Remyelination can occur in lesions of MS, but it becomes increasingly incomplete with age, ultimately leading to failure of repair in most patients and lesions. Therefore, determining the causes of this age-related decline and preventing it is a key goal in the field of regenerative medicine.
To clear the large amount of myelin debris that contains a lot of lipids, especially cholesterol, microglia and monocyte-derived macrophages must generate specific transcriptional responses to promote phagocytosis of myelin debris and lipid metabolism. In lesions of aged rodents, not only is phagocytosis impaired, but degradation and metabolism of tissue debris are also hampered. However, our understanding of the potential reasons why microglia/macrophage responses become insufficient or even maladaptive during aging is incomplete.
Lipoprotein assembly is controlled by the liver X receptor (LXR) transcription factor, which forms heterodimers with the retinoic acid X receptor (RXR). Together, they enhance the expression of apolipoprotein E (APOE), ABCA1, and ABCG1, which are essential for the so-called reverse cholesterol transport pathway. However, the LXR/RXR pathway is not induced in aged rodents. As a result, foamy microglia/macrophages with signs of cholesterol overload accumulate at the site of injury, which impedes the regenerative response of oligodendrocytes and their progenitors. Aging itself is associated with low-grade inflammation, often referred to as "inflammaging," which is characterized by elevated expression of inflammatory markers in microglial subsets, particularly within the white matter. Therefore, during aging, microglia may tend to favor other inflammatory states and, as a result, lose their plasticity in pro-regenerative brain injury responses.
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In this study, the research team tested the hypothesis that age-related epigenetic changes lead to reduced responsiveness and decreased repair function of microglia/macrophages in demyelinating lesions. These epigenetic mechanisms, including DNA methylation and chromatin/histone modifications, are required for the transcriptional program that regulates microglia/macrophage activation. These include histone deacetylases (HDACs) and histone acetyltransferases (HATs), which can reversibly regulate the acetylation state of histones.
Key Histone Deacetylase Target Gene
| HDAC1 | HDAC4 | HDAC7 | HDAC10 | SIRT2 | SIRT5 |
| HDAC2 | HDAC5 | HDAC8 | HDAC11 | SIRT3 | SIRT6 |
| HDAC3 | HDAC6 | HDAC9 | SIRT1 | SIRT4 | SIRT7 |
In addition, the research team explored whether innate immune training in aged mice can restore microglial responses through epigenetic reprogramming to reestablish reparative inflammation. Trained immunity is defined as a state in which a stimulus can persistently prime cells, especially myeloid cells, to respond more strongly to future stimuli. The research team used Bacillus Calmette-Guérin (BCG, a live attenuated Mycobacterium bovis vaccine) to train the innate immune system. BCG was developed for tuberculosis, but has been shown to also reduce morbidity and mortality from unrelated infections and has even been used as a nonspecific immunotherapy in bladder cancer. Given the cross-protection provided by BCG, the research team tested its efficiency and potential epigenetic mechanisms in training microglia to a pro-regenerative response after demyelinating injury during aging.
Overall, the study showed that age-related epigenomic changes impaired the regenerative function of microglia. But innate immune training can reverse these changes and enhance their pro-regenerative capacity in demyelinating injury.
Reference
Tiwari V, et al. Innate immune training restores pro-reparative myeloid functions to promote remyelination in the aged central nervous system. Immunity, 2024.