Sleep-dependent clearance of brain lipids by peripheral blood cells, 2026, Cho et al.

[Colin]

Abstract: Sleep is viewed typically through a brain-centric lens, with little known about the role of the periphery. Here we identify a sleep function for peripheral macrophage-like cells (haemocytes) in the Drosophila circulation, showing that haemocytes track to the brain during sleep and take up lipids accumulated in cortex glia due to wake- associated oxidative damage. Through a screen of phagocytic receptors expressed in haemocytes, we discovered that knockdown of eater—a member of the Nimrod receptor family—reduces sleep. Loss of eater also disrupts haemocyte localization to the brain and lipid uptake, which results in increased brain levels of acetyl-CoA and acetylated proteins, including mitochondrial proteins PGC1α and DRP1. Dysregulation of mitochondria, reflected in high oxidation and reduced NAD+, is accompanied by impaired memory and lifespan. Thus, peripheral blood cells, which we suggest are precursors of mammalian microglia, perform a daily function of sleep to maintain brain function and fitness.

Open access: https://doi.org/10.1038/s41586-025-10050-w

 

[Colin]

Using Drosophila as a model system, we addressed a sleep function for circulating blood cells called haemocytes, 95% of which are macrophage-like plasmatocytes10 that function in immune responses. We show that, at times of high sleep, haemocytes localize to the brain and take up lipids accumulated in cortex glia. As lipid droplets (LDs) in cortex glia reflect the transfer of wake-associated oxidative dam-age from neurons, this uptake by haemocytes is expected to ease metabolic stress in the brain. Indeed, loss of the Eater receptor, which mediates lipid uptake by haemocytes, causes increased acetylation in the brain, along with mitochondrial oxidation and reduced NAD+ levels. Thus, haemocytes, and Eater in particular, act in a sleep-dependent fashion to maintain metabolic homeostasis in the brain.

Discussion

We show here that haemocytes are recruited to the brain during periods of increased sleep and that they clear lipids by means of the Eater protein. If Eater function is impaired, glia accumulate more lipids, and the lipid burden induces metabolic stress with an increase in protein acetylation. This causes mitochondrial dysfunction and metabolic imbalance in the brain (Fig. 6d). In addition to disrupted sleep, memory is impaired and lifespan is shortened. These findings highlight a critical role of brain–periphery interaction, specifically glia–haemocyte lipid transfer, in maintaining brain metabolic health during sleep.

Most studies of immune–sleep interaction have focused on active immune states like inflammation, specific disease or sleep deprived conditions7. In our study we aimed to investigate the interaction between the immune system and sleep in normal daily conditions, where the immune system is not active. We focused on the role of immune cells.

Screening genes expressed in haemocytes for effects on sleep identified the gene eater, which encodes a protein with 32 EGF-like repeats that is involved in cell–cell adhesion, LDL uptake and phagocytosis of Gram-positive bacteria30. eater mutant flies show reduced total sleep and increased sleep fragmentation (Fig. 2a,b) along with memory defects and reduced lifespan (Fig. 6a–c). We were able to completely rescue sleep as well as localization and lipid uptake phenotypes of eater mutants by expression of eater in haemocytes (Fig. 2c,d).

In addition to increased LDs, eater mutant brains had higher levels of acetylated proteins, increased acetyl-CoA levels and reduced NAD+ levels. Although the sequence of these changes remains uncertain, we propose that loss of lipid uptake by Eater leads to an accumulation of LDs, triggering metabolic stress characterized by elevated acetyl-CoA, increased acetylation of key mitochondrial proteins and impaired mitochondrial function. Increased acetyl-CoA levels are also indicative of less beta-oxidation and lower energy production. This fuels a vicious cycle of metabolic stress, oxidative damage and LD accumulation. The consequently reduced levels of NAD+ may further contribute to increased acetylation by impairing NAD-dependent deacetylase enzymes, such as sirtuins46.

Although brain–periphery interactions are currently receiving attention, the role we report here for haemocytes is unprecedented. Our findings suggest that oxidated and acetylated lipids need to be removed from the brain by haemocytes to prevent oxidative damage and preserve the integrity of brain mitochondria. In mammals, microglia are key glial cell types that take up lipids from neurons, and are particularly important in the context of neurodegeneration55. As Drosophila lack microglia, circulating haemocytes may serve an analogous function, acting as intermediaries for lipid uptake and transport/storage and combating stress by accumulating LDs. We find that this is a sleep-dependent process. Although sleep is thought to promote clearance in the brain, the idea that peripheral blood cells contribute to this process represents a critical new perspective.

 

[Creekside]

Interesting, but there's a huge evolutionary gap between flies and humans, so humans might have completely different mechanisms for neural waste removal. It's worth looking into: do ME brain cells accumulate lipids abnormally, or do our blood cells return from the brain with less "stuff" than in non-ME brains?