Research Article: 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

Date Published: July 25, 2017

Publisher: Public Library of Science

Author(s): Jing Xu, Jesse Guardado, Rosemary Hoffman, Hui Xu, Rami Namas, Yoram Vodovotz, Li Xu, Mostafa Ramadan, Joshua Brown, Heth R. Turnquist, Timothy R. Billiar, Karim Brohi

Abstract: BackgroundThe 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 findingsBlunt 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.ConclusionsThese 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.

Partial Text: Severe traumatic injury is a leading cause of death and morbidity in humans between the ages of 1 and 44 years [1,2]. Recent advances in treatments targeting blood loss and coagulopathy have markedly reduced early deaths. However, secondary complications, including acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), and nosocomial infections (NIs) remain significant causes of morbidity in hospitalized trauma patients [3,4]. In patients that progress to organ dysfunction, the lung is the first organ to fail [5,6] as well as being the most common site for NI [7] after severe injury. Although small-animal preclinical models do not mimic all aspects of the complex human response to severe injury [8], reverse translation of novel observations made in humans in well-characterized experimental models has been proposed as an efficient way to gain insights into the mechanisms of immune dysfunction after severe injury [9].

Recent findings indicate that IL33-stimulated ILC2 are a major source of type 2 cytokines in the lung, where these resident innate lymphocytes potently regulate immune responses [24,26,59,60]. While severe trauma often results in acute lung injury, it was unclear if IL33 induced ILC2 cytokine production after systemic injury. It was also unknown if IL33-stimulated ILC2 in the lung shaped detrimental type 2 immune responses after trauma [7]. In determining if IL33 may drive potentially detrimental type 2 immune responses after severe trauma, we found that IL33 levels profoundly and rapidly increase in the blood after injury in humans. This increase was well ahead of subsequent increases in sST2, an endogenous IL33 antagonist [21]. The early increase in IL33 correlated with increased circulating type 2 cytokines, including IL5, and the development of NI and pulmonary dysfunction. Mechanistic studies using a rodent model of severe trauma that recapitulates the rapid escalation in systemic inflammation seen in injured humans revealed analogous findings of early increases in IL33 followed by delayed increases in sST2. The mouse model allowed us to demonstrate that IL33 drives ILC2 production of IL5 that then stimulates neutrophil IL5 in the lung after trauma with shock. Utilizing anti-IL5 antibodies, we established that IL5 was a dominant mediator of early, trauma-induced injury in the lungs. Thus, following a strategy of reverse translating observations made in human trauma into mechanistic studies in a preclinical model allowed us to develop evidence for a role of an IL33–ILC2–IL5–neutrophil axis in the early lung injury response induced by hemorrhagic shock with tissue trauma. These findings also extend the role of ILC2 to acute lung injury responses in noninfectious inflammation and show that IL33-activated ILC2 regulate the local responses of neutrophils recruited to the lung. Most importantly, the current studies identify IL33 and IL5 as potential therapeutic targets to prevent early pulmonary dysfunction in trauma patients.

Source:

http://doi.org/10.1371/journal.pmed.1002365

 

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