Involvement of Pro- and Anti-Inflammatory Cytokines and Chemokines in the Pathophysiology of Traumatic Brain Injury
TL;DR: The role of several cytokines and chemokines following focal and diffuse TBI, as well as the controversies around the use of therapeutic anti-inflammatory treatments versus genetic deletion of cytokine expression are addressed.
About: This article is published in Neurotherapeutics.The article was published on 2010-01-01 and is currently open access. It has received 617 citations till now. The article focuses on the topics: Traumatic brain injury & Neuroprotection.
Citations
More filters
TL;DR: There is a compelling need to revisit the current status of animal models of TBI and therapeutic strategies, as promising neuroprotective drugs identified as being effective in animal TBI models have all failed in Phase II or Phase III clinical trials.
Abstract: Traumatic brain injury (TBI) is a leading cause of mortality and morbidity both in civilian life and on the battlefield worldwide. Survivors of TBI frequently experience long-term disabling changes in cognition, sensorimotor function and personality. Over the past three decades, animal models have been developed to replicate the various aspects of human TBI, to better understand the underlying pathophysiology and to explore potential treatments. Nevertheless, promising neuroprotective drugs that were identified as being effective in animal TBI models have all failed in Phase II or Phase III clinical trials. This failure in clinical translation of preclinical studies highlights a compelling need to revisit the current status of animal models of TBI and therapeutic strategies.
1,149 citations
TL;DR: Findings may provide parallels for studying neurodegenerative disease, with traumatic brain injury patients serving as a model for longitudinal investigations, in particular with a view to identifying potential therapeutic interventions.
Abstract: A single traumatic brain injury is associated with an increased risk of dementia and, in a proportion of patients surviving a year or more from injury, the development of hallmark Alzheimer’s disease-like pathologies However, the pathological processes linking traumatic brain injury and neurodegenerative disease remain poorly understood Growing evidence supports a role for neuroinflammation in the development of Alzheimer’s disease In contrast, little is known about the neuroinflammatory response to brain injury and, in particular, its temporal dynamics and any potential role in neurodegeneration Cases of traumatic brain injury with survivals ranging from 10 h to 47 years post injury (n = 52) and age-matched, uninjured control subjects (n = 44) were selected from the Glasgow Traumatic Brain Injury archive From these, sections of the corpus callosum and adjacent parasaggital cortex were examined for microglial density and morphology, and for indices of white matter pathology and integrity With survival of ≥3 months from injury, cases with traumatic brain injury frequently displayed extensive, densely packed, reactive microglia (CR3/43- and/or CD68-immunoreactive), a pathology not seen in control subjects or acutely injured cases Of particular note, these reactive microglia were present in 28% of cases with survival of >1 year and up to 18 years post-trauma In cases displaying this inflammatory pathology, evidence of ongoing white matter degradation could also be observed Moreover, there was a 25% reduction in the corpus callosum thickness with survival >1 year post-injury These data present striking evidence of persistent inflammation and ongoing white matter degeneration for many years after just a single traumatic brain injury in humans Future studies to determine whether inflammation occurs in response to or, conversely, promotes white matter degeneration will be important These findings may provide parallels for studying neurodegenerative disease, with traumatic brain injury patients serving as a model for longitudinal investigations, in particular with a view to identifying potential therapeutic interventions
810 citations
Cites background from "Involvement of Pro- and Anti-Inflam..."
...…(Aihara et al., 1995; Gentleman et al., 2004; Wilson et al., 2004; Maxwell et al., 2006; Nagamoto-Combs et al., 2007) that contribute to the multitude of cytokines associated with post-traumatic inflammatory cascades (for review see Loane and Byrnes, 2010; Ziebell and Morganti-Kossmann, 2010)....
[...]
...…following TBI has long been viewed as an important contributor to pathology, it is increasingly recog- nized that aspects of acute inflammation may also promote im- portant protective and regenerative effects (Lenzlinger et al., 2001; Browne et al., 2006; Ziebell and Morganti-Kossmann, 2010)....
[...]
TL;DR: A new framework of targeted immunomodulation after TBI is proposed that incorporates factors such as the time from injury, mechanism of injury, and secondary insults in considering potential treatment options and highlights findings that could offer novel therapeutic targets for translational and clinical research.
Abstract: The 'silent epidemic' of traumatic brain injury (TBI) has been placed in the spotlight as a result of clinical investigations and popular press coverage of athletes and veterans with single or repetitive head injuries. Neuroinflammation can cause acute secondary injury after TBI, and has been linked to chronic neurodegenerative diseases; however, anti-inflammatory agents have failed to improve TBI outcomes in clinical trials. In this Review, we therefore propose a new framework of targeted immunomodulation after TBI for future exploration. Our framework incorporates factors such as the time from injury, mechanism of injury, and secondary insults in considering potential treatment options. Structuring our discussion around the dynamics of the immune response to TBI - from initial triggers to chronic neuroinflammation - we consider the ability of soluble and cellular inflammatory mediators to promote repair and regeneration versus secondary injury and neurodegeneration. We summarize both animal model and human studies, with clinical data explicitly defined throughout this Review. Recent advances in neuroimmunology and TBI-responsive neuroinflammation are incorporated, including concepts of inflammasomes, mechanisms of microglial polarization, and glymphatic clearance. Moreover, we highlight findings that could offer novel therapeutic targets for translational and clinical research, assimilate evidence from other brain injury models, and identify outstanding questions in the field.
619 citations
TL;DR: How the neuropathology and neurobiology of CTE in many ways resembles other neurodegenerative illnesses such as Alzheimer's disease is considered, particularly with respect to mismetabolism and aggregation of tau, β-amyloid, and TDP-43.
587 citations
Cites background from "Involvement of Pro- and Anti-Inflam..."
...This microglial response is associated with an upregulation of both pro- and anti-inflammatory genes, chemokines and other inflammatory mediators (Ziebell and Morganti-Kossmann, 2010)....
[...]
TL;DR: The key to developing future anti-inflammatory based neuroprotective treatments for TBI is to minimize the detrimental and neurotoxic effects of neuroinflammation while promoting the beneficial and neurotrophic effects, thereby creating optimal conditions for regeneration and repair after injury.
Abstract: Traumatic brain injury (TBI) remains one of the leading causes of mortality and morbidity worldwide, yet despite extensive efforts to develop neuroprotective therapies for this devastating disorder there have been no successful outcomes in human clinical trials to date. Following the primary mechanical insult TBI results in delayed secondary injury events due to neurochemical, metabolic and cellular changes that account for many of the neurological deficits observed after TBI. The development of secondary injury represents a window of opportunity for therapeutic intervention to prevent progressive tissue damage and loss of function after injury. To establish effective neuroprotective treatments for TBI it is essential to fully understand the complex cellular and molecular events that contribute to secondary injury. Neuroinflammation is well established as a key secondary injury mechanism after TBI, and it has been long considered to contribute to the damage sustained following brain injury. However, experimental and clinical research indicates that neuroinflammation after TBI can have both detrimental and beneficial effects, and these likely differ in the acute and delayed phases after injury. The key to developing future anti-inflammatory based neuroprotective treatments for TBI is to minimize the detrimental and neurotoxic effects of neuroinflammation while promoting the beneficial and neurotrophic effects, thereby creating optimal conditions for regeneration and repair after injury. This review outlines how post-traumatic neuroinflammation contributes to secondary injury after TBI, and discusses the complex and varied responses of the primary innate immune cells of the brain, microglia, to injury. In addition, emerging experimental anti-inflammatory and multipotential drug treatment strategies for TBI are discussed, as well as some of the challenges faced by the research community to translate promising neuroprotective drug treatments to the clinic.
545 citations
Cites background from "Involvement of Pro- and Anti-Inflam..."
...Unfortunately due to space limitations only a small number of promising anti-inflammatory drug treatments can be detailed in this article, and readers are directed to excellent review articles on other preclinical drug treatment strategies for TBI (Shohami et al., 2011; Simard et al., 2010; Ziebell and Morganti-Kossmann, 2010)....
[...]
...…the important role that non-neuronal cells, such as endothelial cells, astrocytes, microglia, oligodendrocytes, play in secondary injury-mediated responses is becoming increasingly recognized (Floyd and Lyeth, 2007; Loane and Byrnes, 2010; Simard et al., 2010; Ziebell and Morganti-Kossmann, 2010)....
[...]
...…only a small number of promising anti-inflammatory drug treatments can be detailed in this article, and readers are directed to excellent review articles on other preclinical drug treatment strategies for TBI (Shohami et al., 2011; Simard et al., 2010; Ziebell and Morganti-Kossmann, 2010)....
[...]
References
More filters
TL;DR: An understanding of intercellular signalling pathways for microglia proliferation and activation could form a rational basis for targeted intervention on glial reactions to injuries in the CNS.
4,372 citations
"Involvement of Pro- and Anti-Inflam..." refers background in this paper
...In addition, however, activated microglia also release various neurotoxic substances, such as reactive oxygen and nitrogen species and glutamate, that may exacerbate neuronal death.(12) Although astrocyte reactivity, proliferation, and migration induced after brain trauma seems to impair axonal regrowth, the presence of these cells around the lesion provides a supporting milieu via the release of neurotrophic factors promoting tissue repair and neurogenesis....
[...]
[...]
TL;DR: Fas ligand (FasL), a cell surface molecule belonging to the tumor necrosis factor family, binds to its receptor Fas, thus inducing apoptosis of Fas-bearing cells.
Abstract: Fas ligand (FasL), a cell surface molecule belonging to the tumor necrosis factor family, binds to its receptor Fas, thus inducing apoptosis of Fas-bearing cells. Various cells express Fas, whereas FasL is expressed predominantly in activated T cells. In the immune system, Fas and FasL are involved in down-regulation of immune reactions as well as in T cell-mediated cytotoxicity. Malfunction of the Fas system causes lymphoproliferative disorders and accelerates autoimmune diseases, whereas its exacerbation may cause tissue destruction.
4,190 citations
"Involvement of Pro- and Anti-Inflam..." refers background in this paper
...membrane members of the TNF–NGF receptor superfamily and share homologous sequences in the extracellular regions.(62,63,66) Besides being a mediator of apoptosis, Fas displays some neuroimmunomodulatory functions....
[...]
TL;DR: Complementary DNAs encoding the cell surface antigen Fas were isolated from a cDNA library of human T cell lymphoma KT-3 cells and revealed that the molecule coding for the Fas antigen determinant is a 319 amino acid polypeptide with a single transmembrane domain.
2,918 citations
TL;DR: Northern hybridization revealed that Fas ligand is expressed in activated splenocytes and thymocytes, consistent with its involvement in T cell-mediated cytotoxicity and in several nonlymphoid tissues, such as testis.
2,600 citations
"Involvement of Pro- and Anti-Inflam..." refers background in this paper
...membrane members of the TNF–NGF receptor superfamily and share homologous sequences in the extracellular regions.(62,63,66) Besides being a mediator of apoptosis, Fas displays some neuroimmunomodulatory functions....
[...]
TL;DR: It has been shown that CSa, formylmethionyl peptides, PAF, and LTB4 act via unrelated receptors, suggesting that neutrophil recruitment can result from the concerted action of multiple stimuli.
Abstract: Introduction Neutrophil accumulation in a tissue is characteristic of inflammation and is observed in a variety of pathological conditions as disparate as infection, trauma, ischemia, and cancer. The process of tissue infiltration is best understood in bacterial infection, where neutrophils are selectively attracted in large numbers to phagocytose and kill the invaders. In other conditions neutrophils are presumably recruited as scavengers of damaged tissue or unwanted extracellular deposits like immune complexes or fibrin. Phagocytosis is accompanied by the release of granule enzymes, superoxide, H202, and a variety of bioactive lipids. Several of these products are required for the killing and digestion of microorganisms. They also induce inflammation and tissue damage, however, which is normally observed after neutrophil accumulation. Several neutrophil chemoattractants have been characterized in recent years; the best known are the anaphylatoxin C5a (1), formylmethionyl peptides of bacterial origin (2), plateletactivating factor (PAF; 3),1 and leukotriene B4 (LTB4; 4). These stimuli have different origins and modes of formation, and their occurrence in disease must thus be expected to vary in accord with the underlying pathophysiological process. C5a is formed upon complement activation via the classical pathway after interaction of microorganisms with antibodies or the formation of immune complexes, or via the alternative pathway after the nonimmune recognition of foreign materials. In bacterial infections, on the other hand, formylmethionyl peptides (which are released by the microorganisms) are likely to be the major attractants. PAFand LTB4 are of special interest because they can be generated by the neutrophils themselves and may thus function as autoor paracrine amplifiers of the responses elicited by other stimuli (5). It has been shown that CSa, formylmethionyl peptides, PAF, and LTB4 act via unrelated receptors, suggesting that neutrophil recruitment can result from the concerted action of multiple stimuli.
1,966 citations