Cytokines and innate inflammation in the pathogenesis of human traumatic brain injury
Highlights
► A wide range of cytokines and growth factors are produced as a result of traumatic brain injury. ► There is evidence for both beneficial and damaging consequences of cytokine production, depending on the concentration and context in which they are produced. ► Blood brain barrier dysfunction is a common consequence of several central nervous system pathologies. ► Cytokine production in blood, cerebrospinal fluid and brain extracellular space is distinct both qualitatively and quantitatively. ► Cytokine action provides a novel and promising therapeutic target following traumatic brain injury.
Introduction
Traumatic brain injury (TBI) is a ubiquitous and devastating condition that is the most common cause of death in those aged below 40 years in the developed world. Current therapeutic strategies have focussed on preventing secondary injury through timely surgical intervention, monitoring and goal directed therapies targeted at relevant physiological parameters (such as intra-cranial pressure, cerebral perfusion pressure, brain tissue oxygen) in the intensive care setting (Helmy et al., 2007b)). This approach has led to improvements in outcome following TBI (Patel et al., 2005), however, without therapeutic strategies that address the underlying pathological mechanisms following TBI there is a limit to the potential gains that can be achieved. This has led to a search for the underlying molecular mediators that result in the pathological consequences of TBI such as blood brain barrier (BBB) breakdown, cerebral oedema (Unterberg et al., 2004) and altered cerebrovascular reactivity (Czosnyka et al., 2009). There has also been a growing realisation that rather than the brain being immunologically privileged, inflammation can play a role in a range of cerebral pathologies such as cerebral ischaemia (Denes et al., 2010). This has led to attempts to better characterise the nature of the inflammatory response and the specific mediators that inflict neuronal injury. Pre-clinical studies have documented numerous examples of cytokine and growth factor production following TBI in rodent models. For example, IL1β has been shown to potentiate neuronal injury (Simi et al., 2007) while vascular endothelial growth factor (VEGF) has been shown to alter blood brain barrier permeability (Nag et al., 2009).
Cytokines are signalling molecules produced by several immune system cells as well as by brain cells, including microglia, astrocytes and neurons. They act as intercellular signalling molecules and are pivotal mediators in several central nervous system (CNS) pathologies. There are several characteristics that are common to most cytokines: they act in cascades, they are endowed with pleiotropic actions and they function synergistically. An additional emerging concept is that cytokines, besides being involved in virtually all CNS conditions, may also have physiological, neuromodulatory and restorative functions. It is now generally accepted that when their concentration exceeds certain levels they contribute to tissue damage and neurodegeneration. Thus cytokines can be roughly divided into pro- and anti-inflammatory, however for most of them these opposing roles seem to coexist and toxic or trophic actions can be observed depending on the exact context (Kadhim et al., 2008, Pinteaux et al., 2009, Popovich and Longbrake, 2008, Suzuki et al., 2009).
Chemokines are a diverse group of heparin-binding proteins with molecular weights in the range of 8–12 kDa which are produced by a range of inflammatory cells and act to recruit and attract leukocytes (Deshmane et al., 2009). They share structural homology and are classified on the basis of the relationship of cysteine residues at the N-terminus: CC (β-chemokines), CXC (α-chemokines), C (γ-chemokines) and CX3C (only one member, fractalkine) where C represents cysteine and X represents any other amino acid residue (Rollins, 1997). They are given a range of other names which can be species specific e.g. CCL2 is given the name monocyte chemoattractant protein 1 (MCP-1) in humans (Semple et al., 2010a). For clarity we have provided the generic nomenclature for each chemokine in the abbreviation section. Together with cytokines and chemokines, a range of other mediators have been implicated in the inflammatory response to TBI, such as complement and these have also been discussed in the relevant sections.
In human TBI, studies have focussed on four approaches to defining the role of inflammatory mediators: blood sampling (both arterial and jugular venous), cerebrospinal fluid (CSF) sampling, microdialysis sampling and direct tissue sampling from ex vivo or post mortem tissue. Each of these approaches has specific advantages and disadvantages, but together a coherent picture is beginning to emerge that has provided novel and promising therapeutic targets. This review aims to provide a synopsis of the current evidence for cytokine and inflammatory mediator production in animal models and in human TBI from three viewpoints. Firstly, we have considered specific cytokines that are implicated in the pathophysiology of TBI. Secondly, we have discussed the special role of the BBB and thirdly, we have considered the various methods that are available to monitor cytokine activity. In particular, we would like to highlight some of the difficulties in interpreting human cytokine data.
Section snippets
Evidence from experimental models of traumatic brain injury
Over the past 2 decades several experimental models have been developed with the aim of reproducing the clinical sequelae of TBI. Models of human focal injury in rodents include the weight drop closed head injury model, the fluid percussion brain injury model, and the controlled cortical impact injury model (Cernak, 2005, Morales et al., 2005). It is generally accepted that no single model reproduces the entire spectrum of events, but rather each of them represents a tool to investigate
Key mediators implicated in human traumatic brain injury
A number of cytokines have been investigated in human TBI, however the bulk of studies focus on relatively few mediators. This bias reflects our understanding of neuroinflammation from pre-clinical studies, however it should not be assumed that other less well-studied mediators are unimportant.
Blood brain barrier function following traumatic brain injury
The BBB is a complex structure that is implicated in the pathogenesis of TBI. It is formed by the neurovascular unit, a conjunction of cerebrovascular endothelial cells, pericytes, astrocytes, and the basal lamina (Ballabh et al., 2004). Apart from small lipophilic molecules, the BBB tightly regulates the exchange of all substances between plasma and the brain interstitium. Ion homeostasis and uptake into the brain of small molecules, such as glucose and amino acids, is conducted via specific
Cytokine sampling methodologies in clinical studies
Several methods exist for sampling inflammatory mediators from the human brain. An appreciation of the relative merits of these techniques is vital in bridging our understanding from animal and in vitro models into human studies. These are discussed extensively below, highlighting the difficulties and limitations associated with each method.
Potential therapeutic avenues and challenges
The growing volume and complexity of literature on inflammatory mediators following TBI in humans has inevitably led to the question as to whether targeting these potentially harmful or reparatory mediators has any therapeutic potential. Several rodent studies have provided promising results however the universal failure of phase III pharmacological neuroprotectant studies (e.g. corticosteroids (Roberts et al., 2004), NMDA antagonists (Morris et al., 1999), dexanabinol (Maas et al., 2006))
Conclusions and future directions
This review has highlighted the growing evidence of cytokine production following human TBI in a range of biological compartments (blood, CSF, brain extracellular space) and the differences between them. We have emphasised the idiosyncrasies of these various sampling methodologies and would encourage detailed reporting of the methods used in all such studies. In particular the method, rate and volume of CSF sampled may be an important determinant of the concentration of mediators within it.
Conflicts of interest
There are no conflicts of interest.
Acknowledgements
AH is supported by the Medical Research Council UK, the Royal College of Surgeons of England, the National Institute for Health Research, UK and the Raymond and Beverley Sackler Fellowship Fund, University of Cambridge. MRG is supported by the Royal College of Surgeons of England and the National Institute for Health Research, UK. KLHC is supported by the National Institute for Health Research Biomedical Research Centre, Cambridge. PJAH is supported by the Academy of Medical Sciences and the
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