Rapid systemic surge of IL-33 after severe human trauma: a prospective observational study

Abstract

Background: Alarmins are considered proximal mediators of the immune response after tissue injury. Understanding their biology could pave the way for development of new therapeutic targets and biomarkers in human disease, including multiple trauma. In this study we explored high-resolution concentration kinetics of the alarmin interleukin-33 (IL-33) early after human trauma.

Methods: Plasma samples were serially collected from 136 trauma patients immediately after hospital admission, 2, 4, 6, and 8 h thereafter, and every morning in the ICU. Levels of IL-33 and its decoy receptor sST2 were measured by immunoassays.

Results: We observed a rapid and transient surge of IL-33 in a subset of critically injured patients. These patients had more widespread tissue injuries and a greater degree of early coagulopathy. IL-33 half-life (t_1/2) was 1.4 h (95% CI 1.2-1.6). sST2 displayed a distinctly different pattern with low initial levels but massive increase at later time points.

Conclusions: We describe for the first time early high-resolution IL-33 concentration kinetics in individual patients after trauma and correlate systemic IL-33 release to clinical data. These findings provide insight into a potentially important axis of danger signaling in humans.

Keywords: Alarmins; Biomarkers; Critical Care; Humans; Immunity; Innate; Interleukin-33; Kinetics; Prospective Studies; Wounds and Injuries.

Fig. 1

IL-33 concentrations in healthy controls and in trauma patients stratified according to New Injury Severity Score (NISS). a IL-33 levels at admission. b IL-33 concentration kinetics in individual critically injured patients (NISS > 24) with detectable IL-33 at admission (one separately colored curve for each patient)

Fig. 2

Critically injured patients (NISS > 24) stratified according to absence (IL-33neg) or presence (IL-33pos) of detectable IL-33 at admission. Differences in a time after injury of first sample, b New Injury Severity Score (NISS), c Injury Severity Score (ISS), d number of ISS regions with injuries, e–h maximum Abbreviated injury scale (AIS) severity score (with 0 representing no injury) in ISS regions Head or neck, Chest, Abdominal or pelvic contents, and Extremities or pelvic girdle, i activated partial thromboplastin time (aPTT) at admission, j international normalized ratio (INR) at admission, k units of packed red blood cells transfused prior to ICU admission, and l base excess at admission, are plotted and compared between the two groups. Black filled circles represent patients with blunt injuries, and red outlined circles represent patients with penetrating injuries. Statistical comparisons were performed with Kruskal–Wallis test with Dunn’s multiple comparison test on the patient groups, with both blunt and penetrating injuries included. Lines indicate median values. ns p ≥ 0.05, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001

Fig. 3

sST2 measured by ELISA in plasma in a selection of trauma patients from the cohort. Concentration curves are plotted in separate panels a (n = 3), b (n = 3), and c (n = 12) according to New Injury Severity Score (NISS) groups. In c (critical injury, NISS > 24), IL-33pos (n = 7) and IL-33neg (n = 5) patients are shown with orange and purple graphs, respectively. Panel d shows both IL-33 (black lines) and sST2 (orange lines) measurements in the IL-33pos NISS > 24 group in the same graph