Neuroimmune Reaction to Sleep Deprivation: A Systematic Review

Sleep deprivation (SD) has long been linked to neuroinflammation, yet a unified mechanistic framework integrating cytokine, microglial, oxidative stress, and neuroendocrine pathways remains underdeveloped. This systematic review synthesizes evidence across human, rodent, and in vitro models to identify a multi-axis mechanism through which sleep loss drives inflammatory signaling in the brain. A systematic search of Google Scholar and ResearchRabbit (1995-July 2025) identified 29 eligible studies, including 13 human studies, 14 rodent studies, and 2 in vitro investigations. Human work primarily quantified systemic inflammatory cytokines, while rodent and cell-based studies provided microglial, ATP-purinergic, and transcriptional pathway data. Across species, sleep deprivation consistently increased Tumor Necrosis Factor-α (TNF-α), Interleukin-1β (IL-1β), and Interleukin-6 (IL-6) signaling and activated canonical inflammatory cascades such as Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Mitogen-activated protein kinase (MAPK). Rodent studies demonstrated convergent microglial remodelling, including P2X purinoceptor 7 (P2RX7) and Purinergic Receptor P2Y (P2Y12) dependent phagocytic activation, ATP-driven process motility, and enhanced synaptic engulfment. Oxidative stress markers and Hypothalamic-pituitary-adrenal axis (HPA-axis) hormones were variably elevated, indicating broader neuroimmune engagement. Across axes, a shared upstream signature emerged: extracellular ATP accumulation, microglial activation, cytokine amplification, and glucocorticoid sensitive modulation of inflammatory tone. These pathways converge on microglial and cytokine networks that collectively reshape synaptic and circuit function during sleep loss. This review highlights conserved mechanistic motifs across models but also identifies limitations, including heterogeneous protocols, limited human microglial data, and lack of formal bias assessment. Together, the synthesized evidence supports a coordinated multi-axis neuroimmune model that explains how sleep deprivation induces neuroinflammation.