Interleukin 37 expression in mice alters sleep responses to inflammatory agents and influenza virus infection

Abstract

Multiple interactions between the immune system and sleep are known, including the effects of microbial challenge on sleep or the effects of sleep loss on facets of the immune response. Cytokines regulate, in part, sleep and immune responses. Here we examine the role of an anti-inflammatory cytokine, interleukin-37 (IL-37) on sleep in a mouse strain that expresses human IL-37b (IL37tg mice). Constitutive expression of the IL-37 gene in the brains of these mice under resting conditions is low; however, upon an inflammatory stimulus, expression increases dramatically. We measured sleep in three conditions; a) under baseline conditions and after 6 h of sleep loss, b) after bolus intraperitoneal administration of lipopolysaccharide (LPS) or IL-1β and c) after intranasal influenza virus challenge. Under baseline conditions, the IL37tg mice had 7% more spontaneous non-rapid eye movement sleep (NREMS) during the light period than wild-type (WT) mice. After sleep deprivation both WT mice and IL37tg mice slept an extra 21% and 12%, respectively, during the first 6 h of recovery. NREMS responses after sleep deprivation did not significantly differ between WT mice and IL37tg mice. However, in response to either IL-1β or LPS, the increases in time spent in NREMS were about four-fold greater in the WT mice than in the IL37tg mice. In contrast, in response to a low dose of mouse-adapted H1N1 influenza virus, sleep responses developed slowly over the 6 day recording period. By day 6, NREMS increased by 10% and REMS increased by 18% in the IL37tg mice compared to the WT mice. Further, by day 4 IL37tg mice lost less weight, remained more active, and retained their body temperatures closer to baseline values than WT mice. We conclude that conditions that promote IL-37 expression attenuate morbidity to severe inflammatory challenge.

The Role, Involvement and Function(s) of Interleukin-35 and Interleukin-37 in Disease Pathogenesis

“…IL-37tg expressing mice were reported to exhibit enhanced sleep responses and improved sleep indices as compared to their wild-type counterparts. Additionally, an overall reduction in mortality (increased survival, return to basal temperature and lesser weight loss) was reported for IL-37tg mice [ 109 ].…”

The interfaces between vitamin D, sleep and pain

“…Its function is still not fully understood, although it is known that this biological phenomenon participates in several processes, e.g., learning, consolidation of memory, inflammation, and metabolic disorders, being essential to good mental and physical health (Walker & Stickgold 2004, Van Cauter et al 2008, Hirotsu et al 2012, Ruiz et al 2012, Garcia et al 2013, Davis et al 2017.…”

Suppression of innate inflammation and immunity by interleukin‐37

“…Nevertheless, transgenic mice expressing the human IL‐37 gene ( IL‐37 ‐transgenic, IL37 ‐tg) have revealed the broad anti‐inflammatory properties of this cytokine. IL37 ‐tg mice exhibit a remarkable protection from endotoxemia, colitis, and spinal cord contusion injury to metabolic syndrome and myocardial ischemia . Similarly, recombinant IL‐37 treatment in wild‐type (WT) mice also affords protection in models of endotoxemia, metabolic syndrome, acute lung injury, spinal cord injury, myocardial infarction, asthma, and ischemic liver disease .…”