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

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.
In a reverse translation study from a human cohort to a mouse trauma model, Timothy Billiar and colleagues investigate the factors mediating immune dysregulation after severe injury.
Author summary Why was this study done? The factors that initiate immune dysregulation after severe injury, including the skewing of the immune system towards type 2 responses, are unknown. Our aim was to determine if interleukin (IL) 33, an alarmin released after tissue injury and a regulator of type 2 immunity, contributes to the early type 2 immune responses after systemic injury. What did the researchers do and find? We measured IL33 and its soluble receptor, soluble suppression of tumorigenicity 2 (sST2), an endogenous antagonist of IL33, in the blood of 472 multiply injured trauma patients. IL33 levels were already markedly elevated on the first blood draw after injury and correlated with increases in IL4, IL5, and IL13 as well as nosocomial infections. Reverse translation experiments using a mouse model of hemorrhagic shock and tissue trauma were carried out to understand the functional link between IL33 and the type 2 cytokine, IL5. IL33 was shown to activate a resident set of innate lymphocytes (group 2 innate lymphoid cells [ILC2]) in the lungs to produce IL5, further leading to neutrophil IL5 production. What do these findings mean? These findings demonstrate the utility of using reverse translation of observations made in humans into mechanistic experimental models that recapitulate key components of the clinical response. IL33 and one of its target cells, ILC2, are identified for the first time as regulators of the early type 2 immune responses after severe injury. The findings include a previously unsuspected role for ILC2 in the regulation of neutrophils and acute lung injury. The findings identify IL33, IL5, or their receptors as potential targets to block early lung injury after polytrauma.