Data from: IL-33 mediated iLC2 activation and neutrophil IL-5 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.