Key Cytokine Pairs Driving Sepsis Damage Identified

One of the main causes of death in the ICU is sepsis, which is the result of an infection that causes the immune system to mistakenly target the body.

Although the mechanisms underlying sepsis have been extensively studied, little is known about the immune system’s cytokines, which are believed to cause serious bodily harm. These proteins aid in the regulation of inflammation, but when the immune system reacts more forcefully than is necessary, it can unleash a “cytokine storm” that damages all tissues and can result in organ failure, tissue damage, and even death.

Researchers at the University of Chicago Pritzker School of Molecular Engineering (PME) measured gene expression in sepsis-affected tissues and organs using a mouse model to gain a better understanding of sepsis and the function of cytokines. The scientists then measured the effects of pairs of cytokines on those same tissues. Michihiro Takahama, an Assistant Professor at Osaka University in Japan and a Former Postdoctoral Fellow in the Chevrier lab, oversaw this work.

Remarkably, the scientists discovered that the majority of the harmful reaction the body had to sepsis was caused by three pairs of cytokines.

We created the first organism-wide map of the effect of sepsis which uncovered a hierarchy within the cytokine storm. And despite the chaotic nature of the storm, the rule that can explain this chaos turned out to be much simpler than we thought.”

Nicolas Chevrier, Assistant Professor and Co-Author, Pritzker School of Molecular Engineering, University of Chicago

The results, which could ultimately lead to new therapies for the condition, were published in Nature Immunology.

Measuring Gene Expression Across Tissues

Antibiotics can be used to treat sepsis, but they can also cause septic shock and even death. The Centers for Disease Control report that sepsis affects one in three hospital deaths.

To better understand the immune system as a whole, according to Chevrier, who seeks to identify the principles guiding the immune system’s actions throughout the body, it is imperative to address the complex elements of a dysregulated immune response, such as sepsis.

Chevrier says, “We know the symptoms of sepsis, but most of the information we have is from blood draws. The knowledge that was lacking the most was what happened inside tissue at the cellular and molecular levels.”

Chevrier and team measured gene expressions across tissues in sepsis-ridden mice models to gain a better understanding of the body’s overall response to sepsis. To better understand the dynamic nature of the condition, measurements were made at six different points in time across various organs, including the skin, heart, and brain. More than 10,000 genes, or almost half of all the genes in the mouse genome, were found to be expressed throughout the body by the team.

The researchers then questioned the extent to which cytokines could be responsible for this gene expression. Researchers did not know which cells and pathways were affected in each tissue, despite the fact that high cytokine levels in sepsis patients are known to be associated with poor outcomes.

Chevrier  says, “It’s hard to disentangle the effects of cytokines which can have many activities depending on which mixtures of cytokines are present in any given tissue and cellular context.”

The team examined each of the six cytokines known to be involved in sepsis individually in an effort to determine which cytokine was causing tissue damage.

Surprisingly, the scientists discovered that no single cytokine could account for the effects of sepsis on the entire organism. However, when the scientist started examining the organism in pairs, the scientist discovered that three cytokines (IL-18, IFN-γ, and IL-1β), when paired with the cytokine TNF, had an effect on gene expression in all tissues that was comparable to sepsis.

Testing to See if Principle Holds True in Humans

The researchers mapped the effects of these cytokine pairs on nearly 200 cell types throughout the body using the cytokine pairs whole-tissue gene expression (PME-seq) and spatial transcriptomic analyses, demonstrating the extensive impact of sepsis on tissues.

The scientist discovered that non-lymphoid tissues recovered more quickly than lymphoid tissues, which may contribute to the explanation of why patients who survive sepsis still have lower survival rates in the years that follow because of compromised immune system performance.

Chevrier aims to investigate if the same cytokine pair principle applies to human tissue. If so, it might open up new treatment options for sepsis. Cytokine blockers have been developed by scientists, but blockers’ efficacy in treating sepsis has been largely lacking. According to Chevrier, the secret to success might lie in combining different blockers for these particular cytokines.