Abstract
The relationship between sleep, metabolism and immune functions has been described, but the cellular components of the interaction are incompletely identified. We previously reported that systemic macrophage depletion results in sleep impairment after sleep loss and in cold environment. These findings point to the role of macrophage-derived signals in maintaining normal sleep. Macrophages exist either in resting form, classically activated, pro-inflammatory (M1) or alternatively activated, anti-inflammatory (M2) phenotypes. In the present study we determined the contribution of M2 macrophages to sleep signaling by using IL-4 receptor α-chain-deficient [IL-4Rα knockout (KO)] mice, which are unable to produce M2 macrophages. Sleep deprivation induced robust increases in non-rapid-eye-movement sleep (NREMS) and slow-wave activity in wild-type (WT) animals. NREMS rebound after sleep deprivation was ~50% less in IL-4Rα KO mice. Cold exposure induced reductions in rapid-eye-movement sleep (REMS) and NREMS in both WT and KO mice. These differences were augmented in IL-4Rα KO mice, which lost ~100% more NREMS and ~25% more REMS compared to WTs. Our finding that M2 macrophage-deficient mice have the same sleep phenotype as mice with global macrophage depletion reconfirms the significance of macrophages in sleep regulation and suggests that the main contributors are the alternatively activated M2 cells.
Highlights
We recently demonstrated that macrophages play a role in sleep signaling in non-inflammatory conditions
We investigated the contribution of M2 macrophages to sleep regulation by using genetically modified mice, in which the pathway of alternative macrophage activation is defective
The amount of sleep is enhanced after sleep deprivation, and EEG slow-wave activity (SWA), which is often regarded as a measure of sleep pressure[1]
Summary
We recently demonstrated that macrophages play a role in sleep signaling in non-inflammatory conditions. Macrophage-depleted animals cannot maintain normal sleep amounts when exposed to moderately cold temperatures These findings show that in the absence of an inflammatory challenge, under two physiological conditions (after short-term sleep loss and at 10 °C ambient temperature), macrophage function/signaling is required for maintaining normal sleep. M2 macrophage deficiency leads to the inability of the animals to maintain normal amounts of recovery sleep after sleep loss and normal amounts of sleep in a mildly cold environment. This is consistent with the hypothesis that alternatively activated, M2, macrophages contribute to the immune signaling of sleep
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