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Microglia, the resident innate immune cells of the central nervous system (CNS), play a role in canonical immune-related functions but also perform a wide range of CNS-tailored functions. Tiwari et al.1 explore one such function: myelin repair, which has implications for several CNS diseases, in particular multiple sclerosis (MS). Microglia participate in this process by phagocytosing myelin debris, which are required for successful remyelination. However, the efficiency of myelin debris clearance by microglia decreases with age, resulting in worse remyelination outcomes.2 This is just one of the many described aging-associated alterations to the neuroimmune system—which is thought to acquire a more pro-inflammatory phenotype—with accompanying transcriptomic and epigenetic alterations.3 The idea that microglia could be “primed” by aging to respond to future (inflammatory) challenges in an exaggerated or atypical manner is in line with the concept of innate immune memory that has been demonstrated in innate immune cells, including microglia.4
In their work, Tiwari et al. tied together these different concepts to contribute to our understanding of how aging impacts the microglial response to demyelination. First, they induced demyelination by focal lysolecithin (lysophosphatidylcholine [LPC]) injection and assessed the impact on microglia. By performing single-cell RNA sequencing (scRNA-seq) on microglia isolated from young (3 months) and aged (15 months) mice, they observed that aging affected the transcriptional responses of microglia to demyelination. Particularly, in aged mice, they observed a reduced expression of genes related to lipid metabolism, immune response, and phagocytosis in microglia isolated from LPC lesions. These gene expression changes in microglia from aged mice were partly explained by alterations in their epigenetic landscape, as analysis using bulk assay for transposase-accessible chromatin (ATAC) sequencing revealed a loss of chromatin accessibility in around 4,000 genes, of which 833 were also found to be downregulated in aged mice in the RNA-seq dataset. These genes were again involved in the innate immune response and lipid metabolism.
To explore whether epigenetic remodeling could rescue the observed aging-associated impaired myelination phenotype, the authors injected mice with the Bacillus Calmette-Guérin (BCG) vaccine. While typically used to immunize against tuberculosis, the vaccine has been shown to alter the epigenetic landscape of immune cells.5 Tiwari et al. observed that pre-vaccination with BCG led to improved remyelination outcomes in aged mice challenged with LPC. In a parallel experiment, increased microglial chromatin accessibility via the microglia-specific deletion of the histone de-acetylating enzymes Hdac1 and Hdac2 also resulted in improved remyelination in aged mice following LPC. Intriguingly, the effects of BCG vaccination were abolished in mice in which microglial expression of Hdac1 and Hdac2 were depleted. This suggests that shared pathway(s) underlie the beneficial effects of BCG vaccination and genetic deletion of Hdac1 and Hdac2, which have been described to play an important role in regulating microglial homeostasis.6 These results were complemented by investigations into molecular targets that could underlie the observed remyelination rescue, which were identified by cross-referencing genes decreased in expression during aging along with those enriched in the histone marks H3K4me3 and H3K27ac following BCG vaccination. The authors paid particular attention to validating a subset of genes identified toward either lipid metabolism or the innate immune response (Apoe, Abca1, Abcg1, Lamp2, B2m, Parp14, Ctsb, Nod1, Irgm1, and Irf7), suggesting that these play a role in microglial remyelination during aging.
This work offers fundamental insight into the interplay between aging, epigenomic changes, and myelin repair failure (Figure 1) but also raises some follow-up questions, perhaps the most intriguing of which is the BCG administration. First used over a hundred years ago, this attenuated virus vaccine has garnered recent attention from observations that it is able to confer protection against other unrelated diseases, e.g., viral infections.7 Although this vaccine used to be required in the late 1900s, its application has been relaxed in recent years, particularly in countries where the rates of tuberculosis continue to decline.8 However, its beneficial effects reported in this and other studies perhaps might rekindle an interest in this vaccine.
Figure 1 Turning back the clock on aging-associated myelin impairments with BCG vaccination
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Particularly in the case of MS, it would be interesting to see whether BCG vaccination would be similarly beneficial in other animal models that mimic both the demyelinating and inflammatory component of the disease. Similarly, while Tiwari et al. laid the groundwork with their characterization of likely transcriptional and epigenetic targets that the BCG injection is acting on, more work needs to be done to better understand the molecular mechanisms that lead to restoration of remyelination in aged animals.
Nonetheless, the insights from this work also provide an interesting piece in the puzzle of understanding MS, whose global incidence follows what is sometimes described as a “latitude gradient.”9 Although BCG clearly would not immunize against MS (as evidenced by its prevalence even in generations of people subject to mandatory BCG vaccination), it would be interesting to assess whether MS progression or severity might somehow be linked to prior vaccination. And while there is much work to do to decipher epidemiological factors involved in the discrepancy between incidence rates around the globe, the results from Tiwari et al. raise the question of whether the increased rates of (tropical) infections from equatorial countries, and subsequent immunization efforts to prevent them, might somehow also contribute to the epidemiological data.
Another question that this work brings to mind is whether BCG would have similarly beneficial effects for other neurological and neurodegenerative diseases with strong neuroimmune components. It seems clear from the current work that BCG is able to modify expression of microglial genes involved in the immune response and lipid metabolism, so what might this mean for diseases where these processes are also afflicted, such as Alzheimer’s disease (AD)? Given the strong neuroimmune component of AD, as well as evidence for the role of the immunological memory in clearing pathology in mouse models that express Aβ,10 it seems likely that there are other diseases for which BCG vaccination, or the biological pathways triggered by it, might be beneficial.
Lastly, the success of this BCG experiment points us toward novel epigenetic mechanisms that contribute to remyelination, which likely overlap with pathways induced during the process of immune memory induction in microglia. However, more work needs to be done to understand how exactly these epigenetic changes in microglia result in improved efficiency of remyelination, e.g., in their interactions with the oligodendrocytes that produce myelin. Another pertinent question involves the timing to induce this unintended protection by BCG vaccination and how long the effects may last. In particular, because mandatory BCG programs are mostly implemented in children, a decay in its effectiveness against other diseases might suggest the utility of booster vaccinations, despite the fact that this is not currently recommended for the prevention of tuberculosis per se.8 As the insights into the exact molecular mechanisms by which BCG restored remyelination capacity generated by this and subsequent studies advance our knowledge, we can hopefully in the future design specific modulatory interventions to promote myelin repair and counteract detrimental changes to this process induced by both disease and aging. With enough understanding of the underlying mechanisms, we might even be able to delineate how to confer this protection independent of BCG vaccination.
The neuroimmune system is complex in its machinations, the minutiae of which we are only now starting to properly appreciate. However, the manuscript from Tiwari et al. also offers hope that we might be able to partially turn back time on some biological processes to restore functions that are progressively lost during aging.
