In a groundbreaking study titled ” A pairwise cytokine code explains the organism-wide response to sepsis” published in Nature Immunology, researchers have embarked on a crucial exploration into the complex molecular and cellular landscape of sepsis, a life-threatening systemic response to infection. The study pioneers an in-depth characterization of the pathogenesis of sepsis by dynamically measuring changes in gene expression across multiple organs. What sets this research apart is its innovative approach to pinpointing the key molecules governing organ states during sepsis by comparing the effects of the infection to those induced by various cytokines.
Sepsis, a life-threatening systemic response to infection, continues to be a leading cause of death in intensive care units worldwide. Despite its significant impact, our understanding of sepsis’s pathogenesis across various organs remains limited. Michihiro Takahama and his colleagues addresses this critical gap by meticulously mapping the organismal response to sepsis over time, analyzing dynamic changes in gene expression across tissues in mouse models. The researchers utilized cytokine injections to unveil a hierarchical cytokine module, including TNF, IL-18, IFN-γ, and IL-1β, which remarkably mirrored the organism-wide response to sepsis. By measuring the impact of cytokines alone or in pairwise combinations on tissue mRNA expression profiles, the study unveils a model where a few key cytokine elements suffice to explain a substantial portion of sepsis effects across tissues. TNF emerges as a central node in this cytokine module, recapitulating many of sepsis’s effects, and its critical role is contextualized by its involvement in various infectious and noninfectious diseases.
The study reveals that the combined effects of specific cytokine pairs, such as tumor necrosis factor plus interleukin-18, interferon-gamma, or interleukin-1β, mimic the broad impact of sepsis across tissues by showcasing changes in the abundance of 195 cell types across nine organs. These findings not only simplify the chaotic cytokine signaling during sepsis but also provide essential spatiotemporal data to construct a mechanistic framework for understanding the disease’s impact on the entire organism.
The organism-wide maps of gene expression uncovered a multitude of changes associated with the initiation and resolution of sepsis, spanning molecular and cellular levels across all organ systems tested. Importantly, the study identified specific cytokine pairs crucial for explaining a large fraction of sepsis’s molecular and cellular effects, shedding light on potential therapeutic targets thereby offering hope for the development of targeted drugs for a disease that currently lacks effective treatments.
References:
Takahama, M., Patil, A., Richey, G. et al. A pairwise cytokine code explains the organism-wide response to sepsis. Nat Immunol (2024). https://doi.org/10.1038/s41590-023-01722-8
