Inferring Tissue-Specific, TLR4-Dependent Type 17 Immune Interactions in Experimental Trauma/Hemorrhagic Shock and Resuscitation Using Computational Modeling.
Inferring Tissue-Specific, TLR4-Dependent Type 17 Immune Interactions in Experimental Trauma/Hemorrhagic Shock and Resuscitation Using Computational Modeling.
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使用计算模型推断实验性创伤/失血性休克和复苏中组织特异性、TLR4 依赖性 17 型免疫相互作用。
DOI：
10.3389/fimmu.2022.908618
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
外伤/失血性休克后复苏（T/HS-R）导致多系统炎症和器官功能障碍，部分原因是损伤相关分子模式分子与toll样受体4 （TLR4）结合。我们对C57BL/6（野生型[WT]）和TLR4缺失（TLR4-/-）小鼠进行实验性T/HS-R（假性骨折+ 2 h休克+ 0-22 h复苏），然后定义心脏、肠道、肺、肝、脾、肾和体循环中20种蛋白水平炎症介质的动态。对7个样本组织的数据进行交叉相关和主成分分析（PCA）表明，与WT样本相比，TLR4-/-样本在一小部分组织区室中表达多种炎症介质，而WT样本中许多炎症介质非特异性地定位于几乎所有区室。我们和其他人之前已经确定了17型免疫细胞在人类创伤中的核心作用。因此，IL-17A与GM-CSF之间的相关性（指示致病性Th17细胞）；IL-17A和IL-10之间（指示非致病性Th17细胞）；在所有研究组织中评估IL-17A和TNF（指示记忆/效应T细胞）。在WT和TLR4-/-小鼠中，在肾脏和肠道中观察到IL-17A与GM-CSF、IL-10和TNF呈正相关。相反，随着时间的推移，在TLR4-/-小鼠的体循环中，病原性和非病原性Th17细胞的变化和动态存在被推断出来，这表明TLR4在这些细胞外排到外周组织中的作用。超图分析（Hypergraph analysis）——用于定义动态的跨室网络——与pca相一致，表明IL-17A在所有采样时间点持续存在于所有组织中，除了在WT组0.5h时在血浆中不存在，这支持了T/HS-R诱导Th17细胞从循环中外排到特定组织的假设。这些分析表明，TLR4和17型免疫在T/HS-R后具有复杂的、特定环境的作用。
Trauma/hemorrhagic shock followed by resuscitation (T/HS-R) results in multi-system inflammation and organ dysfunction, in part driven by binding of damage-associated molecular pattern molecules to Toll-like Receptor 4 (TLR4). We carried out experimental T/HS-R (pseudo-fracture plus 2 h of shock followed by 0-22 h of resuscitation) in C57BL/6 (wild type [WT]) and TLR4-null (TLR4-/-) mice, and then defined the dynamics of 20 protein-level inflammatory mediators in the heart, gut, lung, liver, spleen, kidney, and systemic circulation. Cross-correlation and Principal Component Analysis (PCA) on data from the 7 tissues sampled suggested that TLR4-/- samples express multiple inflammatory mediators in a small subset of tissue compartments as compared to the WT samples, in which many inflammatory mediators were localized non-specifically to nearly all compartments. We and others have previously defined a central role for type 17 immune cells in human trauma. Accordingly, correlations between IL-17A and GM-CSF (indicative of pathogenic Th17 cells); between IL-17A and IL-10 (indicative of non-pathogenic Th17 cells); and IL-17A and TNF (indicative of memory/effector T cells) were assessed across all tissues studied. In both WT and TLR4-/- mice, positive correlations were observed between IL-17A and GM-CSF, IL-10, and TNF in the kidney and gut. In contrast, the variable and dynamic presence of both pathogenic and non-pathogenic Th17 cells was inferred in the systemic circulation of TLR4-/- mice over time, suggesting a role for TLR4 in efflux of these cells into peripheral tissues. Hypergraph analysis – used to define dynamic, cross compartment networks – in concert with PCA-suggested that IL-17A was present persistently in all tissues at all sampled time points except for its absence in the plasma at 0.5h in the WT group, supporting the hypothesis that T/HS-R induces efflux of Th17 cells from the circulation and into specific tissues. These analyses suggest a complex, context-specific role for TLR4 and type 17 immunity following T/HS-R.
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影响因子：
8.8
作者：
Abboud A;Namas RA;Ramadan M;Mi Q;Almahmoud K;Abdul-Malak O;Azhar N;Zaaqoq A;Namas R;Barclay DA;Yin J;Sperry J;Peitzman A;Zamora R;Simmons RL;Billiar TR;Vodovotz Y
通讯作者：
Vodovotz Y
他克莫司对血管化复合材料同种异体移植中组织特异性，蛋白质水平炎症网络的影响。
影响因子：
7.3
作者：
Aral AM;Zamora R;Barclay D;Yin J;El-Dehaibi F;Erbas VE;Dong L;Zhang Z;Sahin H;Gorantla VS;Vodovotz Y
通讯作者：
Vodovotz Y
影响因子：
3.7
作者：
Almahmoud, Khalid;Abboud, Andrew;Vodovotz, Yoram
通讯作者：
Vodovotz, Yoram
影响因子：
8.8
作者：
Benhamou, Ygal;Favre, Julie;Tamion, Fabienne
通讯作者：
Tamion, Fabienne
影响因子：
17.1
作者：
Brown, David;Namas, Rami A.;Vodovotz, Yoram
通讯作者：
Vodovotz, Yoram