<p>Objective Short Sleep Duration is Related to the Peripheral Inflammasome Dysregulation in Patients with Chronic Insomnia</p>

Abstract

Objective: Insomnia with objective short sleep duration (IOSSD) is associated with an increased risk of cardiovascular morbidity, diabetes, neurocognitive impairment, and mortality. Inflammation is believed to be one of the main links between IOSSD and these diseases. The role of nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome in inducing activation of inflammatory signaling in IOSSD is not clear. In this study, we investigated the expression of NLRP3 inflammasome in patients with IOSSD to clarify this issue. Methods: Thirty-six patients with insomnia and 20 age-and sex-matched healthy controls were sequentially recruited. Subjects were categorized into three groups: IOSSD (sleep duration < 6h, n=20), insomnia with objective normal sleep duration (IONSD, sleep duration ≥ 6h, n=16) and healthy controls (n=20). Objective sleep parameters were measured by overnight polysomnography. Peripheral NLRP3 inflammasome protein levels [NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), caspase l] and cytokines [interleukin (IL)-1β and IL-18] were assessed by Western blotting and ELISA, respectively. Results: IOSSD group showed significantly increased protein expressions of ASC and caspase-1 compared to IONSD and healthy controls and significantly increased IL-18 levels compared to healthy controls. On correlation analysis, total sleep time showed an inverse correlation with NLRP3, ASC, IL-18, and IL-1β levels. Wake after sleep onset (WASO) showed a positive correlation with NLRP3, ASC, caspase-1, and IL-1β levels. N3 sleep ratio showed a significant negative correlation with NLRP3, ASC, and IL-18 levels. Conclusion: The current study demonstrated upregulation of NLRP3 inflammasome in IOSSD. Short sleep duration, decreased slow wave sleep, and sleep fragmentation may contribute to dysregulation of NLRP3 inflammasome.

The Putative Role of Neuroinflammation in the Interaction between Traumatic Brain Injuries, Sleep, Pain and Other Neuropsychiatric Outcomes: A State-of-the-Art Review

“…Sleep disturbances as well as short sleep duration have been associated with elevated inflammatory markers [100]. In patients with insomnia, the presence of short sleep, sleep fragmentation, and reduced slow-wave sleep were associated with higher inflammasome levels [101]. Sleep loss has also been shown to impact neuroinflammation and microglia.…”

Sleep deprivation and NLRP3 inflammasome: Is there a causal relationship?

“…A previous study demonstrated the activation of NLRP3 inflammasome in IOSSD patients and proposed that changes in epinephrine and norepinephrine levels in patients may be partly responsible for NLRP3 inflammasome activation via stimulation of leukocyte adrenergic receptors [e.g., Adrenoceptor Beta 2 (ADBR2) and Toll-like-receptor-4 (TLR-4)] and activation of NF-κB-mediated inflammatory signal pathway. In addition, studies have discovered that NLRP3 activity is positively related to short sleep duration and sleep fragmentation ( Wang, 2020 ). In chronic insomnia patients, there is controversy in the findings that show the existence of a link between activation of NLRP3 inflammasome pathway and REM sleep duration ( Wang et al, 2020 ; Aghelan et al, 2022 ).…”

“…In addition, studies have discovered that NLRP3 activity is positively related to short sleep duration and sleep fragmentation ( Wang, 2020 ). In chronic insomnia patients, there is controversy in the findings that show the existence of a link between activation of NLRP3 inflammasome pathway and REM sleep duration ( Wang et al, 2020 ; Aghelan et al, 2022 ).…”

“…However, despite various undesirable side effects including dry mouth, increased number of awakenings, blocked-up nose, mask pressure, and mask leaks, continuous positive airway pressure (CPAP) is the most widely used therapy for this sleep disorder. Currently, no effective strategy is available for prevention of the renal injuries caused by OSA ( Wang et al, 2020 ; Fernandez-Mendoza et al, 2021 ). One study indicated that pharmacological inhibition of mammalian target of rapamycin (mTOR)/NLRP3 axis by rapamycin, alleviates the OSA-induced renal damage ( Liu et al, 2022 ).…”

“…Sleep fragmentation may contribute to dysregulation of NLRP3 inflammasome in IOSSD. Potential mechanisms linking sleep loss and NLRP3 inflammasome may include the activation of sympathetic system, hypothalamus-pituitary-adrenal axis and production of ROS (Wang et al, 2020). 15NLRP3 inflammasome gene expression have a negative correlation with REM sleep duration.…”