Transcriptional response in a sepsis mouse model reflects transcriptional response in sepsis patients

Mortality due to sepsis remains unacceptably high, especially for septic shock patients. Murine models have been used to better understand pathophysiology mechanisms. However, the mouse model is still under debate. Here we investigated the transcriptional response of mice injected with lipopolysaccharide (LPS) and compared it with that of human cells stimulated in vitro with LPS on the one hand, and with that of blood cells in septic patients on the other hand. We identified a molecular signature composed of 2331 genes with an FDR median of 0%. This molecular signature is highly enriched in regulated genes in peritoneal macrophages stimulated with LPS. There is a significant enrichment in several inflammatory signaling pathways, and in disease terms, such as pneumonia, sepsis, systemic inflammatory response syndrome, severe sepsis, an inflammatory disorder, immune suppression, and septic shock. A significant overlap between the genes up-regulated in mouse and human cells stimulated with LPS has been demonstrated. Finally, genes up-regulated in mouse cells stimulated with LPS are enriched in genes up-regulated in human cells stimulated in vitro and in septic patients, who are at high risk of death. Our results support the hypothesis of common molecular and cellular mechanisms between mouse and human sepsis. Twelve C57BL/6SJL mice were purchased from the Charles River Laboratory (L’Arbresle, France). C57BL/6SJL mice were housed under specific pathogen-free conditions and handled in accordance with French and European directives (EU Agreement N° A-13013 03). To model severe form of sepsis, mice were intraperitoneally injected with 200 μL (35 mg/kg) of lipopolysaccharide from Pseudomonas aeruginosa (L9143, Sigma-Aldrich®). The mice were sacrificed by cervical rupture before injection T0 (n=4) and 1 hour after LPS injection during the inflammatory peak T1 (n=4) or 40 hours after LPS injection, just before the death T2 (n=4). Peritoneal cavity cells were collected by peritoneal washes using PBS.