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)-Rora^sg/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.

中文翻译：

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严重创伤后肺反应中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

背景

严重损伤后的免疫抑制和免疫调节异常包括2型免疫反应，表现为损伤后白细胞介素（IL）4，IL5和IL13升高。我们假设IL33是一种在组织损伤后早期释放的警报蛋白，并且是已知的2型免疫调节剂，有助于系统性损伤后的早期2型免疫应答。

方法和发现

纳入I级创伤中心创伤重症监护病房的钝性创伤患者参加了一项观察性研究，其中包括频繁抽血。在血浆中测量IL33的动态变化和致癌性2（sST2）水平的可溶性抑制，并与2型细胞因子和医院感染的水平相关。基于对人类的观察，在复苏的失血性休克和组织创伤（HS / T）的小鼠模型中设计了机械实验。这些实验利用野生型C57BL / 6小鼠，IL33 ^-/-小鼠，B2.C3（Cg）-Rora ^{sg / sg}小鼠缺乏第2组先天淋巴样细胞（ILC2）和C57BL / 6野生型小鼠治疗抗IL5抗体。

严重受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）在入院时随时间推移血浆IL33水平升高，与IL4，IL5和IL13的增加呈正相关（P <0.0001）。sST2水平在受伤后也有所增加，但与IL33相比有所延迟。发生院内感染和器官功能障碍的患者中的IL33和sST2的升高明显高于未受到类似损伤的患者（P <0.05）。在HS / T小鼠模型中进行了机理研究，该模型概括了血浆中IL33的早期增加和sST2的延迟增加（P<0.005）。这些研究确定了IL33在HS / T数小时内诱导肺中ILC2激活的途径。ILC2 IL5上调诱导CXCR2 ⁺肺中性粒细胞进一步表达IL5 ，最终导致早期肺损伤。这项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伤的免疫反应之间潜在差异的影响。同样，进行的研究也不能使我们得出关于IL33对肺功能的影响的结论。

结论

这些结果表明，IL33可能通过ILC2调节嗜中性粒细胞IL5的产生而引发早期有害的2型早期免疫反应。IL33–ILC2–IL5–中性粒细胞轴定义了ILC2在急性肺损伤中的新型调节作用，该作用可能针对易患早期肺功能障碍的创伤患者。