Organism-level analysis of sepsis reveals mechanisms of systemic inflammation. Organism-level analysis of sepsis reveals mechanisms of systemic inflammation

Sepsis is an uncontrolled, systemic response to infection with life-threatening consequences. Our understanding of the pathogenesis of sepsis across organs of the body is rudimentary. Here, using mouse models of sepsis, we generate a dynamic, organism-wide map of the pathogenesis of the disease, revealing the spatiotemporal patterns of well-known and previously unrecognized effects of sepsis on the body. By combining functional perturbations with organism-wide profiling, we discover two interorgan mechanisms that are key to the pathophysiology of sepsis. First, we find that a hierarchical cytokine circuit arising from the pairwise effects of TNF plus IL-18, IFN-γ, or IL-1β suffices to explain a large fraction of the molecular effects of sepsis on the body. Moreover, the effects of these three cytokine pairs on the abundance of nearly two hundred cell types across nine organ types recapitulate half of all the cellular effects of sepsis. Second, we uncover an interorgan pathway whereby a gut-derived, secreted phospholipase, Pla2g5, mediates hemolysis in the blood circulation and contributes to multi-organ failure during sepsis. Thus, a simplifying principle in the systemic behavior of the cytokine network and a lipase misdirected from gut to blood provide fundamental insights to help build a unifying mechanistic framework for the pathophysiological effects of sepsis on the organ systems of the body. Overall design: We performed the experiments and 2 datasets were generated from the following experiments and samples: (1) Lysophosphatidic acid injection, (2) Dexamethasone.

脓毒症（Sepsis）是机体对感染产生的失控性全身炎症反应，可引发致命性后果。目前学界对脓毒症跨器官的发病机制认知仍较为粗浅。本研究借助脓毒症小鼠模型，构建了该疾病发病机制的全机体动态图谱，揭示了脓毒症对机体已知及此前未被发现的作用的时空分布模式。通过将功能扰动实验与全机体组学分析（profiling）相结合，我们发现了两种调控脓毒症病理生理过程的关键器官间互作机制。其一，我们发现由肿瘤坏死因子（TNF）与白细胞介素18（IL-18）、干扰素γ（IFN-γ）或白细胞介素1β（IL-1β）的成对相互作用所构成的分级细胞因子环路，足以解释脓毒症对机体大部分分子层面的影响。进一步研究表明，这三种细胞因子组合对9种器官中近200种细胞类型丰度的调控作用，可复现脓毒症全部细胞效应的一半。其二，我们还揭示了一条器官间信号通路：肠道来源的分泌型磷脂酶Pla2g5可介导血液循环中的溶血反应，并在脓毒症病程中加剧多器官功能衰竭。综上，细胞因子网络系统性行为的简化原则，以及从肠道异位至血液的脂肪酶，为构建阐释脓毒症对机体各器官系统病理生理效应的统一机制框架提供了重要理论依据。整体实验设计：本研究开展了相关实验，并通过以下实验与样本生成了2套数据集：(1) 溶血磷脂酸（Lysophosphatidic acid）注射实验；(2) 地塞米松（Dexamethasone）给药实验。