Elsevier

Injury

Volume 38, Issue 12, December 2007, Pages 1392-1400
Injury

Modulation of immune response by head injury

https://doi.org/10.1016/j.injury.2007.10.005Get rights and content

Summary

Despite the fact that traumatic brain injury (TBI) is a silently growing epidemic, we are yet to understand its multifaceted pathogenesis, where various cellular pathways are initiated in response to both the primary mechanical insult and secondary physiologically mediated injury. Although the brain has traditionally been considered an immunologically privileged site, evidence to the contrary exists in studies of central nervous system (CNS) pathology, in particular TBI. Transmigration of leukocytes following blood brain barrier (BBB) disruption results in activation of resident cells of the CNS, such as microglia and astrocytes, to possess immunological function. Both infiltrating peripheral immune cells and activated resident cells subsequently engage in the intrathecal production of cytokines, important indicators of the presence of neuroinflammation. Cytokines can either promote this neurotoxicity, by encouraging excitotoxicity and propagating the inflammatory response, or attenuate the damage through neuroprotective and neurotrophic mechanisms, including the induction of cell growth factors. Certain cytokines perform both functions, for example, interleukin-6 (IL-6). This review article discusses the notion that the inflammatory response to TBI is no longer a peripherally mediated phenomenon, and that the CNS significantly influences the immunological sequence of events in the aftermath of injury.

Section snippets

The evolution of brain damage in the TBI patient

The often characterised classification of TBI is worth revisiting in the context of the immune response to head injury, as it gives a timeline to the resulting pathological cascades. Primary brain injury refers to the unavoidable brain damage which occurs at the immediate moment of impact, resulting in the disruption of brain parenchyma and cerebral blood vessels. In turn, a further subclassification of focal versus diffuse injury is applied, aiming to typify the distribution of injury to the

The brain's capability to mount an immune response

It has only been in the past 20 years that the CNS has been considered to have the capability to react to external stimuli immunologically. Until this point, the brain was considered “immunologically privileged”, due to the lack of a lympathic system; and moreover, the protection the BBB provided against the passage of cells and soluble molecules.6 There is now evidence for the fallibility of the BBB in this respect, with the transmigration of immune cells, in particular leukocytes, across it

Interleukin-1

Interleukin-1 (IL-1) has been extensively characterised in animal models of TBI (especially in those reproducing focal injury), as a promoter of neuroinflammation.6, 23, 114 Its deleterious effects are arbitrated through the IL-1 receptor (or IL-1R), found strongly expressed on microglia in focal injury, and on neurons and astrocytes in diffuse injury where reactive astrocytosis is acknowledged to evolve early post-trauma.17, 36, 77, 50 Neuronal damage resulting from IL-1 release is not as a

Tumour necrosis factor-α

TNF, like IL-1, was regarded as a purely pro-inflammatory cytokine in the short history of TBI research; however, its potential neuroprotective properties began to emerge at the turn of the century. Such a reputation was gained primarily through its influence on microglia: TNF is well known for its ability to cause increased production and hypertrophy of these native CNS cells, in turn causing paracrine release of itself from this cellular source.40, 97 In doing so, TNF further encourages the

Interleukin-6

Interleukin-6 (IL-6) in many ways is the archetypal ‘dual role’ cytokine in neuroinflammation. It is well known both peripherally and centrally for playing a major role in the acute phase reaction, and subsequently it has many sources, ranging from endothelial cells to neurons.44, 84 Its specific anti-inflammatory properties include the inhibition of TNF and induction of IL-1RA, but its neuroprotective properties extend to the stimulation of NGF production, defence against glutamate-mediated

Interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β)

Both IL-10 and TGF-β are anti-inflammatory cytokines with immunosuppressive attributes, and exert their effects via inhibition of pro-inflammatory cytokines such as TNF, IL-1 and IFN-γ.7, 42, 46, 69 Experimental studies in IL-10 have demonstrated its beneficial effects, with exogenous administration of the cytokine aiding neurological recovery and reducing pro-inflammatory cytokine expression.41 Evidence for the intrathecal production of anti-inflammatory cytokines in TBI patients also exists.

Chemokines

Chemokines initiate recruitment of peripheral leukocytes after TBI, and evidence now exists for their intracerebral production.69, 82 IL-8, otherwise known in rodents as macrophage inflammatory protein-2 (MIP-2), is a powerful chemotactic factor for neutrophils, known to mediate secondary brain injury by induced proteases.69, 92 Increased production of IL-8 in the CSF in patients with severe TBI has been found,45, 47, 54 as early as 6 h of injury.32 Apart from chemotaxis, in our earlier studies,

Conclusions

The duality concept of neuroinflammation in TBI is now a well-acknowledged aspect of trauma research. The conclusions which can be gathered from the literature to date largely revolve around the notion that the immune response in the CNS is dichotomous in its many facets: whether it be the pro- versus the anti-inflammatory reaction, focal versus diffuse injury, the central versus peripheral response, or the acute versus the chronic setting. The CNS is now no longer viewed as an entity which is

Acknowledgements

The research projects in the laboratory of the National Trauma Research Institute are supported by the Victorian Neurotrauma Initiative, the National Health and Medical Research Council, and the Victorian Trauma Foundation.

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