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

• Published in: PLoS medicine 2017-07, Vol.14 (7), p.e1002365
• Main Authors: Xu, Jing, Guardado, Jesse, Hoffman, Rosemary, Xu, Hui, Namas, Rami, Vodovotz, Yoram, Xu, Li, Ramadan, Mostafa, Brown, Joshua, Turnquist, Heth R, Billiar, Timothy R
• Format: Article
• Language: English
• Subjects: Activation analysis; Adult; Aged; Aged, 80 and over; Analysis; Animals; Asthma; Authorship; Biology and Life Sciences; Cell activation; Cohort Studies; CXCR2 protein; Cytokines; Disease Models, Animal; Experiments; Female; Gene Expression Regulation; Hemorrhage; Hospitals; Humans; Immune response; Immunity, Humoral; Immunosuppression; Inflammation; Injuries; Interleukin 1; Interleukin 13; Interleukin 4; Interleukin 5; Interleukin-33 - blood; Interleukin-33 - metabolism; Interleukin-5 - genetics; Interleukin-5 - immunology; Interleukins; Laboratories; Leukocytes (neutrophilic); Lung - immunology; Lungs; Lymphocytes - immunology; Lymphoid cells; Male; Medical research; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Middle Aged; Neutrophils; Nosocomial infection; Nosocomial infections; Pulmonary function tests; Research and Analysis Methods; Respiratory function; Retrospective Studies; Rodents; Roles; Shock, Hemorrhagic - complications; Shock, Hemorrhagic - immunology; Studies; Surgery; Trauma; Tumorigenicity; Wounds and Injuries - etiology; Wounds and Injuries - genetics; Wounds and Injuries - immunology; Young Adult
• ISSN: 1549-1676; 1549-1277; 1549-1676
• DOI: 10.1371/journal.pmed.1002365

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. 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. 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 r