Sleep interruption aggravates sepsis by rewiring the macrophage immune response.

Sepsis is the leading cause of death in hospitals and is very common in intensive care units (ICUs). Sleep is frequently interrupted in the hospital setting, especially within the ICU. Patients who sleep poorly have worse outcomes, such as increased mortality and longer hospital stays; however, the molecular basis remains poorly understood. In this study, we utilized a mouse model to investigate the impact of sleep interruption on subsequent sepsis. We found that sleep interruption aggravated sepsis, as evidenced by higher mortality rates (88% in mice with interrupted sleep vs 57% in mice with normal sleep; P = 0.0045) and worse disease scores. This effect occurred in both females and males. Sleep interruption increased circulating T cells and CD8+ T-cell activation during sepsis. Sleep interruption also increased the levels of serum cytokines (including IL-23 before sepsis was induced, and IL-6, TNF-α, MCP-1, and IL-10 after sepsis), and amplified macrophage cytokine production ex vivo. These ex vivo effects were largely dependent on Toll-like receptor 2 (TLR2), and sleep interruption no longer exacerbated sepsis in TLR2 knockout mice. Interestingly, the effects of sleep interruption on sepsis were reversed by 48 hours of recovery sleep, consistent with a mechanism involving altered gene expression rather than epigenetic changes. RNA sequencing identified 680 genes that were significantly up- or downregulated in macrophages from animals subject to sleep interruption, including multiple genes related to pathogen defense and cytokine signaling. Our study confirms that good sleep is essential to maximize sepsis survival and provides insight into the molecular basis whereby poor sleep alters immune function.