Inducible protein-10, a potential driver of neurally controlled interleukin-10 and morbidity in human blunt trauma

Abstract

Objective: Blunt trauma and traumatic spinal cord injury induce systemic inflammation that contributes to morbidity. Dysregulated neural control of systemic inflammation postinjury is likely exaggerated in patients with traumatic spinal cord injury. We used in silico methods to discern dynamic inflammatory networks that could distinguish systemic inflammation in traumatic spinal cord injury from blunt trauma.

Design: Retrospective study.

Settings: Tertiary care institution.

Patients: Twenty-one severely injured thoracocervical traumatic spinal cord injury patients and matched 21 severely injured blunt trauma patients without spinal cord injury.

Intervention: None.

Measurements and main results: Serial blood samples were obtained from days 1 to 14 postinjury. Twenty-four plasma inflammatory mediators were quantified. Statistical significance between the two groups was determined by two-way analysis of variance. Dynamic Bayesian network inference was used to suggest dynamic connectivity and central inflammatory mediators. Circulating interleukin-10 was significantly elevated in thoracocervical traumatic spinal cord injury group versus non-spinal cord injury group, whereas interleukin-1β, soluble interleukin-2 receptor-α, interleukin-4, interleukin-5, interleukin-7, interleukin-13, interleukin-17, macrophage inflammatory protein 1α and 1β, granulocyte-macrophage colony-stimulating factor, and interferon-γ were significantly reduced in traumatic spinal cord injury group versus non-spinal cord injury group. Dynamic Bayesian network suggested that post-spinal cord injury interleukin-10 is driven by inducible protein-10, whereas monocyte chemotactic protein-1 was central in non-spinal cord injury dynamic networks. In a separate validation cohorts of 356 patients without spinal cord injury and 85 traumatic spinal cord injury patients, individuals with plasma inducible protein-10 levels more than or equal to 730 pg/mL had significantly prolonged hospital and ICU stay and days on mechanical ventilator versus patients with plasma inducible protein-10 level less than 730 pg/mL.

Conclusion: This is the first study to compare the dynamic systemic inflammatory responses of traumatic spinal cord injury patients versus patients without spinal cord injury, suggesting a key role for inducible protein-10 in driving systemic interleukin-10 and morbidity and highlighting the potential utility of in silico tools to identify key inflammatory drivers.

Figure 1

Flow chart of recruitment and study participation. Both groups were matched according to age, gender, and injury severity score (ISS).

Figure 2

Abbreviated Injury Scale (AIS) of traumatic spinal cord injury (TSCI) and non-SCI. Abdominal, extremities, and external injuries were assessed as part of the AIS, and were significantly higher in the non-SCI group as compared to the TSCI group.*P < 0.05 by Student’s t-test.

Figure 3

A. Time course of IL-10. B. Time course of IP-10. C. Time course of IL-17. D. Time course of IL-6. E. Time course of MCP-1. F. Time course of IL-5. G. Time course of IFN-γ. H. Time course of IL-1β. I. Time course of MIP-1β. Mean circulating levels of inflammatory mediators in both traumatic spinal cord injury (TSCI) and non-SCI. Number of patients for each group: TSCI (n = 21), non-SCI (n = 21). The indicated inflammatory mediators were assessed in serial plasma samples obtained at the indicated time points. Values are mean ± SEM. *P< 0.05 by Two-Way ANOVA.

Figure 4

A. Dynamic Bayesian Network analysis (DBN) of traumatic spinal cord injury group suggests IP-10 as the main driver for inflammation that induces interleukin IL-10 production. B. DBN of non-SCI group suggests MCP-1 is the main driver of inflammation.

Figure 5

Analysis of the subgroup with pneumonia. Number of patients for each group: traumatic spinal cord injury (TSCI) with pneumonia (n = 18), non-SCI with pneumonia (n = 10). A. Time course of IL-10. B. Time course of IP-10. C. Time course of IL-6. D. Time course of MCP-1. E. Time course of IFN-γ. F. Time course of IL-1β. G. Time course of IL-17. H. Time course of MIP-1β. Mean circulating levels of inflammatory mediators in both TSCI and non-SCI. The indicated inflammatory mediators were assessed in serial plasma samples obtained at the indicated time points. Values expressed as mean ± SEM *P < 0.05 by Two-Way ANOVA.

Figure 6

A. correlation between IL-10 and IP-10 in traumatic spinal cord injury (TSCI) (n = 21). B. correlation between IL-10 and IP-10 in blunt trauma group without spinal cord injury (non-SCI) (n = 21).

Figure 7

Receiver operator characteristic (ROC) curve for predicting clinical outcome based on IP-10/CXCL10. ROC analysis on circulati ng IP-10 levels suggested that IP-10 levels ≥ 730 pg/ml could separate non-SCI patients with better outcomes vs. non-SCI patients with worse outcomes (sensitivity 96.5% and specificity 98.5%; 95% CI).

Figure 8

A. Plasma IL-10 is significantly (P < 0.001) lower in non-SCI patients with plasma IP-10 < 730 pg/ml (n = 233) vs. non-SCI patients with plasma IP-10 ≥ 730 pg/ml (n = 123). B. Non-SCI patients with plasma IP-10 levels ≥ 730 pg/ml had significantly prolonged hospital length of stay, ICU length of stay, and mechanical ventilator days vs. those with plasma IP-10 < 730 pg/ml. C. TSCI patients with plasma IP-10 levels ≥ 730 pg/ml had significantly prolonged hospital length of stay, ICU length of stay, and mechanical ventilator days vs. those with plasma IP-10 < 730 pg/ml.*P < 0.05 by Student’s t-test.

Figure 8

A. Plasma IL-10 is significantly (P < 0.001) lower in non-SCI patients with plasma IP-10 < 730 pg/ml (n = 233) vs. non-SCI patients with plasma IP-10 ≥ 730 pg/ml (n = 123). B. Non-SCI patients with plasma IP-10 levels ≥ 730 pg/ml had significantly prolonged hospital length of stay, ICU length of stay, and mechanical ventilator days vs. those with plasma IP-10 < 730 pg/ml. C. TSCI patients with plasma IP-10 levels ≥ 730 pg/ml had significantly prolonged hospital length of stay, ICU length of stay, and mechanical ventilator days vs. those with plasma IP-10 < 730 pg/ml.*P < 0.05 by Student’s t-test.

Figure 8

A. Plasma IL-10 is significantly (P < 0.001) lower in non-SCI patients with plasma IP-10 < 730 pg/ml (n = 233) vs. non-SCI patients with plasma IP-10 ≥ 730 pg/ml (n = 123). B. Non-SCI patients with plasma IP-10 levels ≥ 730 pg/ml had significantly prolonged hospital length of stay, ICU length of stay, and mechanical ventilator days vs. those with plasma IP-10 < 730 pg/ml. C. TSCI patients with plasma IP-10 levels ≥ 730 pg/ml had significantly prolonged hospital length of stay, ICU length of stay, and mechanical ventilator days vs. those with plasma IP-10 < 730 pg/ml.*P < 0.05 by Student’s t-test.