A study published in Nature (DOI: 10.1038/s41590-023-01722-8) reveals that the organism-wide response to sepsis can be explained by a pairwise cytokine code involving tumor necrosis factor (TNF), interleukin (IL)-18, interferon-gamma (IFN-γ), and IL-1β. The research used mouse models to analyze gene expression changes across multiple organs in response to sepsis and compared these effects to those of individual and paired recombinant cytokines. The findings show that the combined effects of TNF with IL-18, IFN-γ, or IL-1β closely mimic the impact of sepsis on tissues, suggesting that these cytokine pairs capture the gene, cell, and tissue responses of the host to the disease. The study highlights the complexity of cytokine signaling during sepsis, where the interactions between cytokines can lead to synergistic or antagonistic gene regulation, resulting in nonlinear effects on tissues. By mapping the cellular effects of sepsis and cytokines, the researchers validated their findings using whole-mouse spatial profiling, revealing how these cytokine pairs influence the abundance of 195 cell types across nine organs. The research also demonstrates that the effects of sepsis on immune and non-immune cells are influenced by specific cytokine interactions, with TNF playing a central role in the cytokine module that recapitulates many of the effects of sepsis. The study provides insights into the mechanisms underlying sepsis, including the impact on immune cells, endothelial cells, and other tissue-specific cell types. The findings suggest that understanding these cytokine interactions could lead to the development of targeted therapies for sepsis, as they offer a framework for understanding the complex, systemic response to infection. The study underscores the importance of identifying the causal factors behind the cellular changes observed in sepsis and highlights the need for further research to elucidate the full scope of cytokine interactions and their impact on tissue function.A study published in Nature (DOI: 10.1038/s41590-023-01722-8) reveals that the organism-wide response to sepsis can be explained by a pairwise cytokine code involving tumor necrosis factor (TNF), interleukin (IL)-18, interferon-gamma (IFN-γ), and IL-1β. The research used mouse models to analyze gene expression changes across multiple organs in response to sepsis and compared these effects to those of individual and paired recombinant cytokines. The findings show that the combined effects of TNF with IL-18, IFN-γ, or IL-1β closely mimic the impact of sepsis on tissues, suggesting that these cytokine pairs capture the gene, cell, and tissue responses of the host to the disease. The study highlights the complexity of cytokine signaling during sepsis, where the interactions between cytokines can lead to synergistic or antagonistic gene regulation, resulting in nonlinear effects on tissues. By mapping the cellular effects of sepsis and cytokines, the researchers validated their findings using whole-mouse spatial profiling, revealing how these cytokine pairs influence the abundance of 195 cell types across nine organs. The research also demonstrates that the effects of sepsis on immune and non-immune cells are influenced by specific cytokine interactions, with TNF playing a central role in the cytokine module that recapitulates many of the effects of sepsis. The study provides insights into the mechanisms underlying sepsis, including the impact on immune cells, endothelial cells, and other tissue-specific cell types. The findings suggest that understanding these cytokine interactions could lead to the development of targeted therapies for sepsis, as they offer a framework for understanding the complex, systemic response to infection. The study underscores the importance of identifying the causal factors behind the cellular changes observed in sepsis and highlights the need for further research to elucidate the full scope of cytokine interactions and their impact on tissue function.