0033 Dysregulated sleep and NREM sleep electroencephalogram delta power induced by intermittent hypoxia exposure are attenuated in NLRP3 knockout mice

Abstract Introduction The nucleotide-binding domain leucine rich family pyrin containing 3 (NLRP3) inflammasome protein complex activates caspase-1 to convert the pro-forms of IL-18 and IL-1 beta (IL-1β) into their active forms and is involved in homeostatic sleep and sleep responses to pathogenic stimuli. Intermittent hypoxia (IH) is a hallmark of sleep disordered breathing (SDB) and both IL-18 receptors are associated with SDB in humans. Thus, we hypothesized that NLRP3 inflammasomes are involved in SDB-related sleep disturbances. Methods Sleep architecture was assessed by polysomnography in NLRP3 knockout (KO) and wild-type (WT) mice (N = 8 per group). A gas exchange mixer delivered house air serving as a control or chronic IH that involved 90 second episodic oxygen reductions that consisted of ambient oxygen (21%) with brief hypoxic conditions (~10%) that lasted for 3 seconds for the first 10 h of the light period for 5 consecutive days. Gene expression and protein levels in the brain and lungs were assayed using real-time polymerase chain reaction and enzyme-linked immunosorbent assays, respectively. Results In WT mice, significant increased non-rapid-eye movement (NREM) sleep amounts and NREM sleep electroencephalogram delta power (0.5-4 Hz) were found after 1 day of IH compared to control conditions (p < 0.001). After 5 days of IH, WT mice showed a significant attenuation in NREM sleep amounts and NREM sleep delta power (p < 0.001) and increased wake bout frequency (p = 0.006) when compared to control conditions. However, the IH-induced NREM sleep and NREM sleep delta power enhancements and reductions were attenuated (21-35%) in NLRP3 KO mice compared to WT mice. In WT mice, NLRP3, IL-1β, IL-18 and caspase-1 gene expression, IL-1β and IL-18 protein levels, and caspase-1 activity were significantly increased in the somatosensory cortices, NTS, and lungs after both 1 and 5 days of IH when compared to control conditions (p < 0.05 for all), although NLRP3 KO mice did not exhibit significant differences in molecules downstream of NLRP3 inflammasome activation. Conclusion Our findings indicate that altered NLRP3 inflammasome activation contributes to dysregulated sleep occurring from IH and likely is involved in sleep disturbances in SDB. Support (If Any) VA Career Development Aware IBX002823, VA Merit BX004500, NIH/NIMH 1R21MH125242, NIH/NHLBI R03 HL154284, and NIH/NHLBI R35 HL135818. JTM received partial salary compensation and funding from Merck Investigator Sponsored Programs but has no conflict of interest with this work.