Key points:
- By examining gene expression patterns in a mouse model, researchers developed an organism-wide map of the effects of sepsis.
- While no single cytokine could explain all effects of sepsis, the cytokine TNF paired with any of three specific cytokines – IL-18, IFN-γ, and IL-1β – had the same effect on gene expression across tissues as sepsis.
- In the future, the team hopes to test the cytokine pair principle in human tissue and develop new therapeutic interventions for sepsis.
Sepsis – when an infection causes the immune system to improperly target the body – can cause septic shock and death. Many studies have examined the causes of sepsis, but none have fully characterized the role of immune system cytokines. Cytokines normally control inflammation, but a “cytokine storm” can occur during sepsis, leading to tissue injury, organ failure, and death.
In a new study, published in Nature Immunology, researchers developed an organism-wide map of the effects of sepsis and determined the organization within the cytokine storm.
The research team measured gene expression across tissues in mouse models with sepsis. Measuring in the brain, heart, and skin across six time points provided insight into the dynamic nature of sepsis. Based on their measurements, the team identified more than 10,000 genes that were expressed across the entire body.
Next, the researchers characterized which cytokines caused tissue damage by focusing on six cytokines known to be involved in sepsis. They found that no single cytokine could explain the organism-wide effects of sepsis. However, investigation of pairwise cytokine combinations revealed that three cytokines – IL-18, IFN-γ, and IL-1β – paired with the cytokine TNF had the same effect on gene expression across tissues as sepsis.
After uncovering these cytokine pairs, the researchers employed whole-tissue gene expression and spatial transcriptomic analyses to map the pairs’ effect on nearly 200 different cell types. They found that non-lymphoid tissues returned to normal faster than lymphoid tissues.
“We created the first organism-wide map of the effect of sepsis which uncovered a hierarchy within the cytokine storm,” explained co-author Nicolas Chevrier, professor at the University of Chicago. “Despite the chaotic nature of the storm, the rule that can explain this chaos turned out to be much simpler than we thought.”
In the future, the team hopes to test the cytokine pair principle in human tissue and develop new therapeutic interventions for sepsis. Using combinations of blockers for the specific cytokines identified in this study may be a key to successful treatment.