Table 1.

Human Studies of Neuroinflammation after TBI: Triggers / Brakes

Inflammatory mediator	Tissue / Fluid	Time Course	Association with clinical outcome(s)	Other	Ref
Triggers / Brakes
Adenosine	CSF ECF	Increased within hours of injury Rapidly decline over 12–24h	Pediatric: No association with outcome after severe TBI Adult: Higher level in patients that died after severe TBI	A1AR gene variants associated with post-traumatic epilepsy Increased CSF adenosine associated with jugular vein desaturation	222–224
Complement	CSF	Peak day 1 post-injury, decline day 2–7	Adult: Increased MAC level associated with BBB dysfunction in severe TBI	C3 and Factor B increased relative to controls	58,225
	Tissue	Increased in tissue resected 2–82h post-injury	Unknown	C3-mRNA also detected in penumbra, suggesting a contribution of local synthesis	57
Glutamate	CSF ECF	Multiple courses described Most common peak day 1, decline day 2–3	Pediatric: Higher level associated with poor 6mo-GOS in severe TBI Adult: Increase in ECF glutamate associated with poor outcomes	Increased glutamate associated with age < 4 and child abuse Hourly levels not affected by transient hemodynamic or ICP change	41,226–228
HMGB1	CSF	No change over time	Pediatric: Higher level associated with unfavorable 6 month GOS in severe TBI Adults: Increased level associated with high ICP	Not associated with age or mechanism of injury	27,28
	Tissue	Translocated to cytoplasm of cells in contused area at 30min – 1d Localized to cytoplasm of phagocytic microglia at 2–20d	Unknown	HMGB1 receptor, RAGE, expression also increased in contused area in phagocytic microglia	229
NLRP1	CSF	Unknown	Adult: Higher level in patients with unfavorable 5 month GOS in moderate to severe TBI	Adaptor protein ASC also increased in CSF of TBI patients	230
Caspase-1	CSF	Unknown	Adult: Higher level in patients with unfavorable 5mo-GOS in moderate to severe TBI	Identified by p20 subunit suggests activated form of enzyme	230
	Tissue	Pro-caspase-1 is cleaved to active form on day 1	Unknown		231
mtDNA	CSF	Peak day 1, declined on day 3, though still above control	Pediatric: Higher levels associated with unfavorable 6mo- GOS in severe TBI	Positively correlated with HMGB1 level	52

Abbreviations: TBI – traumatic brain injury; CSF – Cerebrospinal fluid; ECF – Extracellular fluid; A1AR – adenosine receptor A1; MAC – membrane attack complex; ICP – intracranial pressure; HMGB1 – high mobility group box 1; RAGE – receptor for advanced glycation endproducts; NLRP1 – NACHT, LRR and PYD domains-containing protein 1; GOS – Glasgow Outcome Scale; mtDNA – mitochondria DNA; BBB – blood brain barrier; GCS – Glasgow Coma Scale