Sleep and immune function: glial contributions and consequences of aging

Abstract

The reciprocal interactions between sleep and immune function are well-studied. Insufficient sleep induces innate immune responses as evidenced by increased expression of pro-inflammatory mediators in the brain and periphery. Conversely, immune challenges upregulate immunomodulator expression, which alters central nervous system-mediated processes and behaviors, including sleep. Recent studies indicate that glial cells, namely microglia and astrocytes, are active contributors to sleep and immune system interactions. Evidence suggests glial regulation of these interactions is mediated, in part, by adenosine and adenosine 5'-triphosphate actions at purinergic type 1 and type 2 receptors. Furthermore, microglia and astrocytes may modulate declines in sleep-wake behavior and immunity observed in aging.

Figure 1

Glial modulation of sleep and immune interactions. Cellular activity causes ATP release into the extracellular space via neurotransmission and gliotransmission. Extracellular ATP induces rapid effects once metabolized to adenosine by ectonucleotidases such as CD39 and CD73. Adenosine binds to purine type 1 receptors like the A₁R to modulate EEG slow wave activity and NREMS, as well as local neuroinflammation and excitotoxicity. Slower effects of extracellular ATP occur through direct activation of purine type 2 receptors such as the P2X₇R prominently expressed on microglia. P2X₇R activation induces processing and release of cytokines including, but not limited to, IL-1β and TNFα. Cytokines subsequently act on their respective receptors to activate transcription factors like nuclear factor-κB (not shown) which modulates neuroinflammation, physiological and pathological sleep, and gene transcription of receptors such as the A₁R, AMPA, and the AMPA subunit GluR1. This overly simplified schematic focuses on the featured topics of this mini-review, and thus, not all cellular and molecular components are fully represented. AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; GluR1, glutamate receptor 1.