0219 Mice Lacking IL-18 have Reduced Sleep and Slow-waveActivityResponses to Sleep Promoting Stimuli

Abstract

Introduction: Interleukin (IL)-18 is a pro-inflammatory cytokine that is a member of the IL-1 family. IL-18 is activated by inflammatory stimuli including the gram negative bacterial cell wall component lipopolysaccharide (LPS) and influenza-both of which alter sleep and slow-wave activity (SWA). IL-18 is also enhanced in individuals with pro-inflammatory conditions such as sepsis, type 2 diabetes, and cancer. We previously found that the nucleotide-binding domain leucine-rich family pyrin containing 3 (NLRP3) inflammasome is enhanced by sleep loss and LPS. NLRP3 inflammasome activation is a primary mechanism for the activation of both IL-1beta (IL-1β) and IL-18 by its corresponding pathogen associated molecular patterns including extracellular adenosine tri-phosphate and LPS. Thus, we examined sleep architecture responses to pro-inflammatory sleep promoting stimuli in mice lacking IL-18 [i.e., IL-18 knockout (KO) mice]. Methods: IL-18 KO and wild-type (WT) control mice were sleep deprived for 6 h prior to dark onset using the gentle handling method, allowed to sleep ad libitum, or intracerebroventricular infusions of LPS, IL-18 protein, or vehicle. Polysomnography was performed in the mice after the preceding treatment and sleep states and SWA were analyzed. Significance was set at p < 0.05. Results: IL-18 KO and WT mice both had significantly enhanced non-rapid eye movement (NREM) sleep and SWA responses after sleep deprivation or LPS compared to ad libitum sleep conditions and vehicle administration, respectively. However, a significant interaction was observed between genotypes and the treatments where WT mice exhibited significant enhancements in NREM sleep and SWA after sleep deprivation and LPS compared to IL-18 KO mice. Infusion of IL-18 significantly enhanced NREM sleep and SWA in both IL-18 KO and WT mice rescuing the sleep and SWA response of IL-18 KO mice. Conclusion: These data indicate that IL-18 is, in part, involved in homeostatic sleep regulation. Moreover, these findings are consistent with the idea that IL-18 like IL-1β is, in part, activated by NLRP3 inflammasomes to promote sleep and SWA by its respective pathogen associated molecular patterns and pattern recognition receptors.