Inflammatory cytokine and chemokine profiles are associated with patient outcome and the hyperadrenergic state following acute brain injury

Abstract

Background: Traumatic brain injury (TBI) elicits intense sympathetic nervous system (SNS) activation with profuse catecholamine secretion. The resultant hyperadrenergic state is linked to immunomodulation both within the brain and systemically. Dysregulated inflammation post-TBI exacerbates secondary brain injury and contributes to unfavorable patient outcomes including death. The aim of this study was to characterize the early dynamic profile of circulating inflammatory cytokines/chemokines in patients admitted for moderate-to-severe TBI, to examine interrelationships between these mediators and catecholamines, as well as clinical indices of injury severity and neurological outcome.

Methods: Blood was sampled from 166 isolated TBI patients (aged 45 ± 20.3 years; 74.7 % male) on admission, 6-, 12-, and 24-h post-injury and from healthy controls (N = 21). Plasma cytokine [interleukin (IL)-1β, -2, -4, -5, -10, -12p70, -13, tumor necrosis factor (TNF)-α, interferon (IFN)-γ] and chemokine [IL-8, eotaxin, eotaxin-3, IFN-γ-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, -4, macrophage-derived chemokine (MDC), macrophage inflammatory protein (MIP)-1β, thymus activation regulated chemokine (TARC)] concentrations were analyzed using high-sensitivity electrochemiluminescence multiplex immunoassays. Plasma catecholamines [epinephrine (Epi), norepinephrine (NE)] were measured by immunoassay. Neurological outcome at 6 months was assessed using the extended Glasgow outcome scale (GOSE) dichotomized as good (>4) or poor (≤4) outcomes.

Results: Patients showed altered levels of IL-10 and all chemokines assayed relative to controls. Significant differences in a number of markers were evident between moderate and severe TBI cohorts. Elevated IL-8, IL-10, and TNF-α, as well as alterations in 8 of 9 chemokines, were associated with poor outcome at 6 months. Notably, a positive association was found between Epi and IL-1β, IL-10, Eotaxin, IL-8, and MCP-1. NE was positively associated with IL-1β, IL-10, TNF-α, eotaxin, IL-8, IP-10, and MCP-1.

Conclusions: Our results provide further evidence that exaggerated SNS activation acutely after isolated TBI in humans may contribute to harmful peripheral inflammatory cytokine/chemokine dysregulation. These findings are consistent with a potentially beneficial role for therapies aimed at modulating the inflammatory response and hyperadrenergic state acutely post-injury.

Fig. 1

Plasma cytokine and chemokine concentrations in moderate and severe TBI patients sampled over 24 h. Cytokines interleukin (IL)-10 (a), tumor necrosis factor (TNF)-α (b). Chemokines eotaxin, eotaxin-3, interferon-gamma induced protein (IP)-10, IL-8, monocyte chemoattractant protein (MCP)-1, -4, macrophage-derived chemokine (MDC), macrophage inflammatory protein (MIP)-1β, and thymus and activation regulated chemokine (TARC) (c–k) in moderate (GCS 9–12, n = 33, open squares) and severe (GCS 3–8, n = 133, closed squares) TBI patients within the first 24 h of hospital admission vs. healthy control subjects (no TBI, n = 21, open circles). Lines represent the median and interquartile range. *p < 0.05 vs. healthy controls by Kruskal-Wallis. ^† p < 0.05 vs. moderate TBI by Mann-Whitney U test

Fig. 2

Plasma cytokine and chemokine concentrations in TBI patients stratified according to the 6-month GOSE. I nterleukin (IL)-1β, -10, tumor necrosis factor (TNF)-α (a–c). IL-8, monocyte chemoattractant protein (MCP)-1, macrophage-derived chemokine (MDC) (d–f) in TBI patients with unfavorable (GOSE 1–4, n = 102) vs. favorable (GOSE 5–8, n = 61) 6-month neurological outcome. Lines represent the median and interquartile range. ^* p < 0.05 vs. favorable outcome by Mann-Whitney U test

Fig. 3

Plasma cytokine and chemokine concentrations in TBI patients stratified by mortality. Cytokines interleukin (IL)-1β, -10, tumor necrosis factor (TNF)-α (a–c). Chemokines IL-8, interferon-gamma producing protein (IP)-10, monocyte chemoattractant protein (MCP)-1, -4, macrophage-derived chemokine (MDC), macrophage inflammatory protein (MIP)-1β, thymus and activation regulated chemokine (TARC), and eotaxin (d–k) in TBI patients who died (n = 45) vs. those who lived (n = 119). Lines represent the median and interquartile range. ^* p < 0.05 vs. lived by Mann-Whitney U test

Fig. 4

Plasma cytokine and chemokine concentrations in TBI patients according to the cause of death. I nterleukin (IL)-1β, -10, tumor necrosis factor (TNF)-α (a–c). IL-8, interferon-gamma producing protein (IP)-10, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-1β (d–g) in TBI patients who survived (n = 119) vs. those who died by neurologic death (n = 28) or by non-neurologic organ failure (n = 17). Boxes represent the median and interquartile ranges, and whisker plot lines represent the range. *p < 0.05 vs. patients who survived; ^† p < 0.05 vs. patients who succumbed to neurologic death, by Kruskal-Wallis