Guilty Molecules, Guilty Minds? The Conflicting Roles of the Innate Immune Response to Traumatic Brain Injury

Table 1

Key studies highlighting the dual roles of proinflammatory cytokines after traumatic brain injury.

(a)

IL-1β
Finding	Clinical/experimental	Experimental setting	Reference
Acutely upregulated after TBI	Clinical	Cerebral microdialysis; adult and pediatric patient CSF	[100, 102, 116, 117]
Peripheral administration after TBI results in larger lesions and impaired behavioural outcomes	Experimental (rat)	Fluid percussion injury	[118]
Expression exacerbated and prolonged by secondary insult	Experimental (rat)	Diffuse axonal injury with posttraumatic hypoxia	[27]
Causes BBB dysfunction in vivo	Experimental (rat; in vitro)	Cerebral endothelial cells	[119]

(b)

TNF
Finding	Clinical/experimental	Study methodology	Reference
High levels observed acutely after injury	Clinical	Cerebral microdialysis, adult patient CSF	N [102, 120, 121]
Acutely upregulated in rats after focal TBI	Experimental (rat)	Controlled cortical injury; lateral fluid percussion	[115, 122]
Administration causes BBB dysfunction and increased recruitment of peripheral leukocytes	Experimental (rat, newborn piglet, rat; in vitro)	Healthy animals/cerebral endothelial cells	N [119, 123, 124]
Inhibition of TNF ameliorates BBB dysfunction	Experimental (rat)	Controlled cortical injury	[125]
Deficiency of TNF/TNF-R causes exacerbated BBB damage and impairs long-term recovery	Experimental (mouse)	Controlled cortical injury	N [126, 127]
Expression exacerbated and prolonged by secondary insult	Experimental (rat)	Diffuse axonal injury with posttraumatic hypoxia	[27]

(c)

IL-6
Finding	Clinical/experimental	Study methodology	Reference
CSF levels correlate with improved outcome	Clinical	Adult and pediatric patient CSF	[128, 129]
Production within 24 h localised to neurons	Experimental (rat)	Diffuse axonal injury	[130]
IL-6 deficient mice have heightened neurodegeneration, increased oxidative stress, poor behavioural recovery	Experimental (mouse)	Controlled cortical injury; aseptic cerebral injury	[158–160]

(d)

GM-CSF
Finding	Clinical/experimental	Study methodology	Reference
Significantly upregulated in brain tissue within minutes of TBI	Clinical	Postmortem brain tissue	[131]
Promotes neuronal stem cell differentiation in vitro	Experimental (rat; in vitro)	Neural stem cell culture	[132]
Promotes tissue sparing when administered in conjunction with IL-3	Experimental (rat)	Stab-wound injury	[133]
Minimises tissue damage and promotes behavioural recovery	Experimental (rat)	Spinal cord contusion	[134, 135]