Bidirectional regulation of sleep and immunity: mechanisms and pathological significance

Sleep and immunity interact through a highly coordinated “sleep-immune axis” to maintain physiological homeostasis. Sleep optimizes immune cell trafficking through neuroendocrine pathways, suppresses sympathetic nervous activity to mitigate inflammation, and regulates microglial polarization to sustain neuroimmune balance. In return, immune signals shape sleep architecture: pro-inflammatory cytokines activate thalamic neurons to enhance slow-wave sleep (SWS), microglia inhibit norepinephrine release via the P2Y12-Gi-Ca²⁺ pathway, and peripheral immune activation feeds back to regulate sleep-wake cycles. Dysregulation of this bidirectional axis constitutes a pathogenic link to cardiovascular diseases, neurodegenerative disorders, autoimmune diseases, and metabolic disorders. Sleep loss reprograms immune phenotypes, amplifies systemic inflammation, and compromises immune surveillance, whereas immune dysregulation, such as TREM2 deficiency or autoimmune injury to orexinergic neurons, directly impairs sleep regulation. Therapeutic interventions targeting key nodes, including STING pathway activation, adenosine-modulating light therapy, and gut microbiota modulation, hold promise for restoring sleep–immune homeostasis and improving outcomes in comorbid disease states.