IL33-mediated ILC2 activation and neutrophil IL5 production in the lung response after severe trauma: A reverse translation study from a human cohort to a mouse trauma model.
IL33-mediated ILC2 activation and neutrophil IL5 production in the lung response after severe trauma: A reverse translation study from a human cohort to a mouse trauma model.
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严重创伤后肺部反应中 IL33 介导的 ILC2 激活和中性粒细胞 IL5 产生：从人类队列到小鼠创伤模型的反向翻译研究
DOI：
10.1371/journal.pmed.1002365
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发表时间：
2017-07
期刊：
影响因子：
15.8
通讯作者：
Billiar TR
中科院分区：
文献类型：
--
作者：
Xu J;Guardado J;Hoffman R;Xu H;Namas R;Vodovotz Y;Xu L;Ramadan M;Brown J;Turnquist HR;Billiar TR
严重损伤后的免疫抑制和免疫失调包括2型免疫反应，表现为损伤后早期白细胞介素（IL） 4、IL5和IL13的升高。我们假设IL33是组织损伤后早期释放的一种警报蛋白，也是一种已知的2型免疫调节因子，有助于全身性损伤后的早期2型免疫反应。方法和研究结果对一所一级创伤中心重症监护病房收治的钝性创伤患者进行观察性研究，包括频繁采血。检测血浆中il - 33和可溶性致瘤性抑制2 （sST2）水平的动态变化，并与2型细胞因子水平和医院感染相关。在人体观察的基础上，设计了复苏失血性休克和组织创伤（HS/T）小鼠模型的机制实验。实验采用野生型C57BL/6小鼠、IL33-/-小鼠、B6小鼠。C3(Cg)-Rorasg/sg小鼠缺乏2组先天淋巴样细胞（ILC2）， C57BL/6野生型小鼠用抗il5抗体处理。严重损伤的人类钝性创伤患者（n = 472，平均损伤严重程度评分[ISS] = 20.2）入院时血浆IL33水平升高，随时间推移与IL4、IL5和IL13水平升高呈正相关（P < 0.0001）。与IL33相比，损伤后sST2水平也增加，但延迟。在发生医院感染和器官功能障碍的患者中，IL33和sST2的升高明显高于未发生类似损伤的患者（P < 0.05）。在HS/T小鼠模型中进行了机制研究，重现了血浆中IL33的早期升高和sST2的延迟升高（P < 0.005）。这些研究确定了在HS/T发生数小时内，IL33在肺中诱导ILC2激活的途径。ILC2 IL5上调通过CXCR2+肺中性粒细胞进一步诱导IL5表达，最终导致早期肺损伤。本研究的主要局限性是人类研究成分的描述性，以及人类和小鼠对多发创伤的免疫反应的潜在差异的影响。此外，所进行的研究也不允许我们得出il - 33对肺功能影响的结论。结论这些结果表明，IL33可能通过ILC2调节中性粒细胞IL5的产生而引发创伤后早期有害的2型免疫反应。il33 - ILC2 - il5中性粒细胞轴确定了ILC2在急性肺损伤中的新调控作用，可能针对早期肺功能障碍的创伤患者。
Background The immunosuppression and immune dysregulation that follows severe injury includes type 2 immune responses manifested by elevations in interleukin (IL) 4, IL5, and IL13 early after injury. We hypothesized that IL33, an alarmin released early after tissue injury and a known regulator of type 2 immunity, contributes to the early type 2 immune responses after systemic injury. Methods and findings Blunt trauma patients admitted to the trauma intensive care unit of a level I trauma center were enrolled in an observational study that included frequent blood sampling. Dynamic changes in IL33 and soluble suppression of tumorigenicity 2 (sST2) levels were measured in the plasma and correlated with levels of the type 2 cytokines and nosocomial infection. Based on the observations in humans, mechanistic experiments were designed in a mouse model of resuscitated hemorrhagic shock and tissue trauma (HS/T). These experiments utilized wild-type C57BL/6 mice, IL33-/- mice, B6.C3(Cg)-Rorasg/sg mice deficient in group 2 innate lymphoid cells (ILC2), and C57BL/6 wild-type mice treated with anti-IL5 antibody. Severely injured human blunt trauma patients (n = 472, average injury severity score [ISS] = 20.2) exhibited elevations in plasma IL33 levels upon admission and over time that correlated positively with increases in IL4, IL5, and IL13 (P < 0.0001). sST2 levels also increased after injury but in a delayed manner compared with IL33. The increases in IL33 and sST2 were significantly greater in patients that developed nosocomial infection and organ dysfunction than similarly injured patients that did not (P < 0.05). Mechanistic studies were carried out in a mouse model of HS/T that recapitulated the early increase in IL33 and delayed increase in sST2 in the plasma (P < 0.005). These studies identified a pathway where IL33 induces ILC2 activation in the lung within hours of HS/T. ILC2 IL5 up-regulation induces further IL5 expression by CXCR2+ lung neutrophils, culminating in early lung injury. The major limitations of this study are the descriptive nature of the human study component and the impact of the potential differences between human and mouse immune responses to polytrauma. Also, the studies performed did not permit us to make conclusions about the impact of IL33 on pulmonary function. Conclusions These results suggest that IL33 may initiate early detrimental type 2 immune responses after trauma through ILC2 regulation of neutrophil IL5 production. This IL33–ILC2–IL5–neutrophil axis defines a novel regulatory role for ILC2 in acute lung injury that could be targeted in trauma patients prone to early lung dysfunction.
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影响因子：
2.4
作者：
Díaz-Jiménez D;De la Fuente M;Dubois-Camacho K;Landskron G;Fuentes J;Pérez T;González MJ;Simian D;Hermoso MA;Quera R
通讯作者：
Quera R
DOI：
10.1111/cea.12491
发表时间：
2015-07
期刊：
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
影响因子：
--
作者：
Ather JL;Foley KL;Suratt BT;Boyson JE;Poynter ME
通讯作者：
Poynter ME
影响因子：
5.5
作者：
Bunt, Stephanie K.;Clements, Virginia K.;Ostrand-Rosenberg, Suzanne
通讯作者：
Ostrand-Rosenberg, Suzanne
影响因子：
4.4
作者：
KleinJan, Alex;Wolterink, Roel G. J. Klein;Hendriks, Rudi W.
通讯作者：
Hendriks, Rudi W.
影响因子：
6.6
作者：
Barbosa, Izabela Guimaraes;Morato, Isabela Boechat;Teixeira, Antonio Lucio
通讯作者：
Teixeira, Antonio Lucio