Sleep interruption aggravates sepsis by rewiring the macrophage immune response.

Summary

In mice, prior sleep interruption markedly worsened sepsis outcomes, increasing mortality and inflammatory cytokines, with effects largely dependent on TLR2 signaling in macrophages. Notably, 48 hours of recovery sleep reversed these effects, and RNA-seq revealed extensive transcriptional reprogramming of macrophages.

Key Findings

• Sleep interruption increased sepsis mortality (88% vs 57%; P=0.0045) and worsened disease scores in mice.
• Serum cytokines (IL-23 pre-sepsis; IL-6, TNF-α, MCP-1, IL-10 post-sepsis) and CD8+ T-cell activation were elevated.
• Macrophage cytokine amplification ex vivo was largely TLR2-dependent; TLR2 knockout abrogated the exacerbation.
• Forty-eight hours of recovery sleep reversed the detrimental effects, consistent with gene expression changes.
• RNA-seq identified 680 differentially expressed macrophage genes linked to pathogen defense and cytokine signaling.

Clinical Implications

Promoting sleep continuity and minimizing nocturnal disruptions in ICU settings may attenuate harmful immune reprogramming in sepsis. These data prioritize trials of sleep-preserving bundles and exploration of TLR2-targeted modulation.

Limitations

• Preclinical mouse model limits direct generalizability to human ICU settings.
• Sleep interruption paradigm may not fully recapitulate complex ICU sleep disturbances or comorbidities.

Future Directions

Prospective ICU trials testing multimodal sleep-preserving bundles and mechanistic studies of TLR2-pathway modulation in human myeloid cells during sepsis.