High-Mobility Group Box 1 (HMGB1) Is Elevated Systemically in Persons with Acute or Chronic Traumatic Spinal Cord Injury

Abstract

Inflammation in traumatic spinal cord injury (SCI) has been proposed to promote damage acutely and oppose functional recovery chronically. However, we do not yet understand the signals that initiate or prolong inflammation in persons with SCI. High-Mobility Group Box 1 (HMGB1) is a potent systemic inflammatory cytokine-or damage-associated molecular pattern molecule (DAMP)-studied in a variety of clinical settings. It is elevated in pre-clinical models of traumatic spinal cord injury (SCI), where it promotes secondary injury, and strategies that block HMGB1 improve functional recovery. To investigate the potential translational relevance of these observations, we measured HMGB1 in plasma from adults with acute (≤ 1 week post-SCI, n = 16) or chronic (≥ 1 year post-SCI, n = 47) SCI. Plasma from uninjured persons (n = 51) served as controls for comparison. In persons with acute SCI, average HMGB1 levels were significantly elevated within 0-3 days post-injury (6.00 ± 1.8 ng/mL, mean ± standard error of the mean [SEM]) or 4-7 (6.26 ± 1.3 ng/mL, mean ± SEM), compared with controls (1.26 ± 0.24 ng/mL, mean ± SEM; p ≤ 0.001 and p ≤ 0.01, respectively). In persons with chronic SCI who were injured for 15 ± 1.5 years (mean ± SEM), HMGB1 also was significantly elevated, compared with uninjured persons (3.7 ± 0.69 vs. 1.26 ± 0.24 ng/mL, mean ± SEM; p ≤ 0.0001). Together, these data suggest that HMGB1 may be a common, early, and persistent danger signal promoting inflammation in individuals with SCI.

Keywords: damage-associated molecular pattern; high mobility group box 1; inflammation; spinal cord injury.

FIG. 1.

High-Mobility Group Box 1 (HMGB1) levels are elevated in persons with acute spinal cord injury (SCI). In all panels, gray dotted bar indicates HMGB1 value obtained from uninjured persons (n = 51). (A) Black bars indicate HMGB1 values obtained at the day post-injury (DPI) indicated. (B) Black bars indicate peak HMGB1 values obtained within 0–3 or 4–6 DPI. (C) Black bars indicate peak HMGB1 values obtained from persons with neurologically complete or incomplete injuries. (D) Black bars indicate peak HMGB1 values obtained from persons with injuries at levels T5 and above or T6 and below. Bars indicate values of participants from indicated group (mean ± standard error of the mean). Numbers over each bar indicate the number of participants from whom the data was obtained. Asterisks indicate statistical significance: ****p ≤ 0.0001, ***p ≤ 0.001, **p ≤ 0.01, *p ≤ 0.05 with respect to uninjured group.

FIG. 2.

High-Mobility Group Box 1 (HMGB1) levels are elevated in persons with chronic spinal cord injury (SCI). In all panels, gray hatched bar indicates mean HMGB1 value obtained from uninjured persons (n = 51). (A) Black bars indicate HMGB1 values obtained from persons with chronic SCI. (B) Black bars indicate HMGB1 values obtained from persons living with SCI for less or more than 5 years. (C) Black bars indicate HMGB1 values obtained from persons with injuries according to their American Spinal Injury Association Impairment Scale (AIS) grade. (D) Black bars indicate HMGB1 values obtained from persons with injuries at levels T5 and above or T6 and below. Bars indicate values of participants from indicated group (mean ± standard error of the mean). Numbers over each bar indicate the number of participants from whom the data was obtained. Asterisks indicate statistical significance: ****p ≤ 0.0001, ***p ≤ 0.001, **p ≤ 0.01, *p ≤ 0.05 with respect to uninjured group. YPI, years post-injury.