Circadian-immune crosstalk in insomnia disorder: mechanisms and therapeutic implications
Abstract
Insomnia disorder (ID) is a common sleep-wake disorder characterized by persistent difficulty initiating or maintaining sleep, early-morning awakening, or non-restorative sleep, accompanied by daytime functional impairment. ID has traditionally been explained by the hyperarousal model, which emphasizes cognitive, emotional, cortical, neuroendocrine, and autonomic overactivation. However, this model alone does not fully account for the chronic persistence, relapse tendency, and multisystem associations of ID. Emerging evidence suggests that circadian rhythm disruption, impaired melatonin signaling, hypothalamic-pituitary-adrenal (HPA) axis activation, autonomic imbalance, and low-grade inflammation may also contribute to the development and maintenance of ID. Available evidence indicates that sleep disturbance is more consistently associated with selected inflammatory markers, particularly C-reactive protein (CRP) and interleukin-6 (IL-6), whereas findings for tumor necrosis factor-alpha (TNF-α) remain less consistent. The circadian system regulates sleep, endocrine function, metabolism, and immune-inflammatory activity through the suprachiasmatic nucleus, melatonin and cortisol rhythms, peripheral clock genes, and rhythmic immune-cell responses. Disruption of this temporal network may alter melatonin secretion, inflammatory rhythmicity, and stress-related neuroendocrine responses, thereby contributing to the persistence of insomnia symptoms. Compared with previous reviews…
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