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Reversal of immune-cell shutdown protects the ageing brain
Immune cells called macrophages are found in almost every tissue, and are crucial for maintaining organ health and providing a first line of defence against disease-causing organisms. The energy demands of macrophages increase drastically when they are activated, and so they rebalance or enhance their two main energy-producing metabolic pathways (glycolysis and oxidative phosphorylation) to quickly fuel an effective immune response1. Writing in Nature, Minhas et al.2 report that macrophages shut down these metabolic pathways during ageing, severely compromising macrophage function and, in turn, brain health. This work has implications not only for the preservation of brain health during ageing, but also for conditions such as Alzheimer’s disease or sepsis, in which similar maladaptive macrophage states could be common.
As we age, chronic, low-grade inflammation develops in most people3. One inflammatory signalling protein whose levels rise not only during ageing4 but also during neurodegenerative disease5 is prostaglandin E2 (PGE2). Minhas et al. set out to investigate whether PGE2 might cause age-associated changes in macrophages. Interestingly, the authors found increased production of PGE2 in human and mouse macrophages themselves — both in the brain and elsewhere in the body (the periphery). This led to the activation of PGE2’s receptor protein EP2 in the cells, which in turn resulted in suppression of oxidative phosphorylation and glycolysis. The resulting energy-deficient state both limited the beneficial functions of macrophages and increased inflammation.
To determine whether these changes could cause age-associated cognitive dysfunction, the authors examined a mouse strain in which EP2 receptor levels were reduced exclusively in macrophages in the body and brain, and treated mice with an EP2 inhibitor. Strikingly, EP2 inhibition restored macrophage metabolism to youthful levels in both settings, reducing inflammation in the periphery and brain, and alleviating cognitive decline (Fig. 1). These results indicate that (at least in mice) macrophage dysfunction during ageing affects brain health, and that normal cell function can be restored by reversing metabolic shutdown in the cells.
Figure 1 | Reversing metabolic shutdown in aged macrophages. Immune cells called macrophages are found throughout the body (the periphery) and in the brain, where they are called microglia. a, Minhas et al.2 report, that during ageing, peripheral macrophages and microglia produce more of the protein prostaglandin E2 (PGE2), which binds to EP2 receptors on the cells’ membranes. They demonstrate that activation of this signalling pathway leads to metabolic dysfunction in the cells, and so to systemic chronic inflammation and cognitive decline. b, The authors inhibited the EP2 receptor in two ways. First, they used a genetic approach to reduce levels of EP2 in both macrophages and microglia. Second, they inhibited the receptor pharmacologically — but only in the periphery. Under both conditions, EP2 inhibition improved metabolic function in peripheral macrophages and microglia, reducing inflammation and restoring cognitive ability. The mechanism by which peripheral inhibition of EP2 leads to changes in microglia is unknown (dashed arrow).
Minhas and colleagues went on to dive deeper into the metabolic rewiring of aged macrophages. They found that such macrophages favoured energy storage in the form of glycogen (a large glucose polymer) over the use of glucose for energy production through glycolysis or oxidative phosphorylation. Although glycogen normally serves as a fuel reserve, aged macrophages did not seem to use this reserve, despite their energy-deficient state.
It is unclear why aged macrophages store extra glycogen, but dendritic cells, a related cell type, use their glycogen stock to fuel their earliest inflammatory responses6. Therefore, it is conceivable that aged macrophages increase glycogen storage so that they can mount a stronger immune response during acute inflammatory activation. In line with this idea, aged microglia (brain macrophages) are well known to be primed — that is, to respond more strongly to inflammatory insults than do young microglia7. Minhas and co-workers did not directly analyse whether microglial priming is enabled by increased glycogen stores. However, this possibility would certainly be worth investigating, because some evidence suggests that exacerbated immune responses in the aged brain contribute to neurodegenerative disease7.
Notably, there is also evidence for a role of microglial metabolic dysfunction in brain disease, particularly in Alzheimer’s disease. The risk of developing Alzheimer’s increases several-fold in people who carry mutations in the microglial receptor protein TREM2. In mice, TREM2 deficiency causes breakdown of microglial metabolism and exacerbation of Alzheimer’s pathology8. Furthermore, chronic exposure of microglia to aggregated amyloid-β protein, a hallmark of Alzheimer’s disease, leads to the breakdown of oxidative phosphorylation and glycolysis in these cells in mice9. In both cases, enhancing microglial metabolism leads to less-severe Alzheimer’s pathology in the mouse models.
In sepsis (a condition that results from excessive inflammation in response to infection), PGE2 levels also increase9 and long-term cognitive deficits often develop7. Here, macrophages enter a state called immune paralysis, which is also characterized by suppression of both oxidative phosphorylation and glycolysis1,10. Thus, the cellular shutdown of macrophages during sepsis or during ageing and neurodegenerative disease might be a response to excessive or chronic immune stimulation, respectively. This adaptation would be beneficial from an evolutionary perspective because it would protect an organism from a hyperactive immune response that could cause tissue damage. However, in the context of an ageing organism, it seems to predispose the brain to dysfunction or even degeneration. Whether macrophage immune states are indeed similar across these different conditions remains to be investigated.
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