Elsevier

Brain Research Reviews

Volume 48, Issue 2, April 2005, Pages 388-399
Brain Research Reviews

Review
Closed head injury—an inflammatory disease?

https://doi.org/10.1016/j.brainresrev.2004.12.028Get rights and content

Abstract

Closed head injury (CHI) remains the leading cause of death and persisting neurological impairment in young individuals in industrialized nations. Research efforts in the past years have brought evidence that the intracranial inflammatory response in the injured brain contributes to the neuropathological sequelae which are, in large part, responsible for the adverse outcome after head injury. The presence of hypoxia and hypotension in the early resuscitative period of brain-injured patients further aggravates the inflammatory response in the brain due to ischemia/reperfusion-mediated injuries. The profound endogenous neuroinflammatory response after CHI, which is phylogenetically aimed at defending the intrathecal compartment from invading pathogens and repairing lesioned brain tissue, contributes to the development of cerebral edema, breakdown of the blood–brain barrier, and ultimately to delayed neuronal cell death. However, aside from these deleterious effects, neuroinflammation has been recently shown to mediate neuroreparative mechanisms after brain injury as well. This “dual effect” of neuroinflammation was the focus of extensive experimental and clinical research in the past years and has lead to an expanded basic knowledge on the cellular and molecular mechanisms which regulate the intracranial inflammatory response after CHI. Thus, head injury has recently evolved as an inflammatory and immunological disease much more than a pure traumatological, neurological, or neurosurgical entity. The present review will summarize the so far known mechanisms of posttraumatic neuroinflammation after CHI, based on data from clinical and experimental studies, with a special focus on the role of pro-inflammatory cytokines, chemokines, and the complement system.

Introduction

In industrialized nations, closed head injury (CHI) represents the leading cause of death and residual neurological impairment in young patients under the age of 45 years [74], [75]. Despite advances in research and improved neurointensive care in the last decade, the clinical outcome of severely head-injured patients is still poor and the mortality rate remains as high as 35–40% [42], [60], [75]. The extent of residual brain damage is determined by primary and secondary injuries. While primary brain injury results from mechanical forces applied to skull and brain at the time of impact, leading to either focal or diffuse injury patterns, secondary brain injury represents a consequence of complicating processes initiated by the primary insult, whereby the main risk factors are constituted by early hypoxia and hypotension during the resuscitative period [42], [65], [75]. These secondary events induce neuroinflammation by activation of the innate immune response, e.g., via complement activation, thereby triggering a profound host-mediated inflammatory response within the intracranial compartment. Among the crucial endogenous mediators of neuroinflammation are pro-inflammatory cytokines [29], [37], [85], [114], chemokines [37], [103], and complement anaphylatoxins [11], [88], [120] which mediate chemotaxis of blood-derived leukocytes across the blood–brain barrier (BBB) into the subarachnoid space [48]. These recruited inflammatory cells further contribute to the development of secondary brain injury by exacerbating and perpetuating the inflammatory response in the injured brain, e.g., through the oxidative burst of neutrophils associated with the release of proteolytic and neurotoxic enzymes [109], [145]. The full range of events which contribute to the development of secondary brain damage after CHI is very complex and not yet fully understood. This is mainly due to the variety of endogenous mediators released in the intracranial compartment after trauma and the complexity of their interactions and time-dependent regulation of agonistic and antagonistic functions. Since non-inflammatory mechanisms of secondary neuronal cell death, such as excitotoxicity and apoptosis, are not part of the scope of the present review, the reader is referred to excellent review articles published elsewhere [68], [72], [100].

Although the central nervous system (CNS) has been historically defined as an “immunologically privileged organ” due to its tight separation from peripheral circulation by the BBB, research efforts in recent years have revealed that the CNS is a rich source of inflammatory mediators. Resident cells of the brain, such as neurons, astrocytes, and microglia, have been shown to be capable of synthesizing essentially all immune mediators of the “peripheral” immune system, including cytokines, chemokines and complement activation proteins, and to express the receptors for these immune mediators [4], [7], [49], [83], [103], [104]. It is nowadays generally accepted that a physiological immune surveillance is present in the CNS and that a potent immune response can be induced within the injured brain. The controversial concept of a “dual role” of neuroinflammation emerged in recent years, based on experimental studies demonstrating a neurotoxic as well as neuroprotective function of inflammatory mediators, depending on the kinetics of regulation and expression in the time-course after trauma [4], [69], [81], [86], [108], [114]. The present review will outline the current understanding on the mechanisms of posttraumatic neuroinflammation after head injury with a focus on the “dual” aspect regarding concomitant beneficial and deleterious effects of the trauma-induced inflammatory response in the injured brain.

Section snippets

Complement activation in the injured brain: a new challenge from an “old” cascade

Activation of complement through either the classical, the alternative, or the lectin (mannose-binding protein; MaBP) pathways plays a key role in innate immune responses aimed at protection against infection or tissue injury (Fig. 1) [21]. The generation of proteolytic complement fragments leads to pleiotropic inflammatory effects, such as opsonization of invading pathogens for phagocytosis, induction of increased vascular permeability, recruitment of phagocytic cells, augmentation of the

Chemokines: crucial regulators of cellular trafficking in the injured brain

Aside from the chemotactic activity of anaphylatoxins resulting from post-injury complement activation, chemokines represent the most crucial mediators of leukocyte recruitment in the injured brain [4], [5], [23], [44], [103], [104], [132]. As mentioned above, the intracranial infiltration of blood-derived leukocytes is an important event contributing to neuroinflammation in the injured CNS [105]. Most importantly, the recruitment of neutrophils across the BBB has been shown to be detrimental

Dual role of cytokine-mediated neuroinflammation

Cytokines are central mediators of neuroinflammation following head injury [1], [29], [37], [85]. A vast array of adverse effects was ascribed to these low molecular weight polypeptides, whereby recent data have revised this assumed downright detrimental character [69], [86], [114], [137]. The proposed “dual role” of cytokines in the pathophysiology of CHI has been thoroughly investigated in recent years, particularly regarding mediators such as TNF, IL-6, and members of the IL-1 family. We

Conclusions

The pathophysiological sequelae of CHI are highly complex and far from being sufficiently understood. Vast research efforts in recent years have established head trauma as a predominantly inflammatory and immunological disease. The complement system, cytokines and chemokines represent established crucial “players” in the concert of trauma-induced neuroinflammation. However, up to the present, most of the underlying mechanisms of “go” vs. “no-go” decisions for neuroinflammation and

Acknowledgments

We would like to acknowledge the significant contribution of several collaborators throughout the past years on the projects outlined in this review: Scott R. Barnum (University of Alabama at Birmingham, AL, USA), Cristina and Thomas Kossmann (Monash University, Melbourne, Australia), Esther Shohami (Hebrew University of Jerusalem, Israel), and coworkers from our own laboratory, Imogen Bleif and Silvia Saft (Charité, Campus Benjamin Franklin, Berlin). Part of this work was supported by a grant

References (145)

  • K. Fassbender et al.

    Temporal profile of release of interleukin-1beta in neurotrauma

    Neurosci. Lett.

    (2000)
  • R.A. Gadient et al.

    Interleukin-6 (IL-6)—a molecule with both beneficial and destructive potentials

    Prog. Neurobiol.

    (1997)
  • P. Gasque et al.

    Complement components of the innate immune system in health and disease in the CNS

    Immunopharmacology

    (2000)
  • E.H. Hausmann et al.

    Selective chemokine mRNA expression following brain injury

    Brain Res.

    (1998)
  • S.J. Hopkins et al.

    Cytokines and the nervous system. I: expression and recognition

    Trends Neurosci.

    (1995)
  • K.L. Keeling et al.

    Local neutrophil influx following lateral fluid-percussion brain injury in rats is associated with accumulation of complement activation fragments of the third component (C3) of the complement system

    J. Neuroimmunol.

    (2000)
  • S.M. Knoblach et al.

    Early neuronal expression of tumor necrosis factor-alpha after experimental brain injury contributes to neurological impairment

    J. Neuroimmunol.

    (1999)
  • T. Kossmann et al.

    Interleukin-6 released in human cerebrospinal fluid following traumatic brain injury may trigger nerve growth factor production in astrocytes

    Brain Res.

    (1996)
  • T. Kossmann et al.

    Elevated levels of the complement components C3 and factor B in ventricular cerebrospinal fluid of patients with traumatic brain injury

    J. Neuroimmunol.

    (1997)
  • M. Lacy et al.

    Expression of the receptors for the C5a anaphylatoxin, interleukin-8 and FMLP by human astrocytes and microglia

    J. Neuroimmunol.

    (1995)
  • R.R. Leker et al.

    Cerebral ischemia and trauma—different etiologies yet similar mechanisms: neuroprotective opportunities

    Brain Res. Rev.

    (2002)
  • A.K. Liou et al.

    To die or not to die for neurons in ischemia, traumatic brain injury and epilepsy: a review on the stress-activated signaling pathways and apoptotic pathways

    Prog. Neurobiol.

    (2003)
  • N.J. Lynch et al.

    Microglial activation and increased synthesis of complement component C1q precedes blood–brain barrier dysfunction in rats

    Mol. Immunol.

    (2004)
  • P. Megyeri et al.

    Recombinant human tumor necrosis factor alpha constricts pial arterioles and increases blood–brain barrier permeability in newborn piglets

    Neurosci. Lett.

    (1992)
  • J.E. Merrill et al.

    Cytokines in inflammatory brain lesions: helpful and harmful

    Trends Neurosci.

    (1996)
  • T.E. Mollnes et al.

    Complement in inflammatory tissue damage and disease

    Trends Immunol.

    (2002)
  • B.P. Morgan et al.

    Expression of complement in the brain: role in health and disease

    Immunol. Today

    (1996)
  • S. Nataf et al.

    Complement anaphylatoxin receptors on neurons: new tricks for old receptors?

    Trends Neurosci.

    (1999)
  • S. Nataf et al.

    Expression of the anaphylatoxin C5a receptor in the oligodendrocyte lineage

    Brain Res.

    (2001)
  • L. Probert et al.

    TNF-alpha transgenic and knockout models of CNS inflammation and degeneration

    J. Neuroimmunol.

    (1997)
  • S.M. Allan et al.

    Cytokines and acute neurodegeneration

    Nat. Rev., Neurosci.

    (2001)
  • S.M. Allan et al.

    Cortical cell death induced by IL-1 is mediated via actions in the hypothalamus of the rat

    Proc. Natl. Acad. Sci. U. S. A.

    (2000)
  • H.A. Arnett et al.

    TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination

    Nat. Neurosci.

    (2001)
  • A.A. Babcock et al.

    Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS

    J. Neurosci.

    (2003)
  • S.R. Barnum

    Inhibition of complement as a therapeutic approach in inflammatory central nervous system (CNS) disease

    Mol. Med.

    (1999)
  • S.R. Barnum

    Complement in central nervous system inflammation

    Immunol. Res.

    (2002)
  • M.J. Bell et al.

    Interleukin-6 and interleukin-10 in cerebrospinal fluid after severe traumatic brain injury in children

    J. Neurotrauma

    (1997)
  • B.M. Bellander et al.

    Activation of the complement cascade and increase of clusterin in the brain following a cortical contusion in the adult rat

    J. Neurosurg.

    (1996)
  • B.M. Bellander et al.

    Complement activation in the human brain after traumatic head injury

    J. Neurotrauma

    (2001)
  • J.W. Berman et al.

    Localization of monocyte chemoattractant peptide-1 expression in the central nervous system in experimental autoimmune encephalomyelitis and trauma in the rat

    J. Immunol.

    (1996)
  • A.J. Bruce et al.

    Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors

    Nat. Med.

    (1996)
  • I.L. Campbell et al.

    Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6

    Proc. Natl. Acad. Sci. U. S. A.

    (1993)
  • C. Casarsa et al.

    Intracerebroventricular injection of terminal complement complex causes inflammatory reaction in the rat brain

    Eur. J. Immunol.

    (2003)
  • N. Davoust et al.

    Receptor for the C3a anaphylatoxin is expressed by neurons and glial cells

    Glia

    (1999)
  • H.P. Eugster et al.

    IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis

    Eur. J. Immunol.

    (1998)
  • I. Farkas et al.

    A neuronal C5a receptor and an associated apoptotic signal transduction pathway

    J. Physiol.

    (1998)
  • K. Fassbender et al.

    Interferon-gamma-inducing factor (IL-18) and interferon-gamma in inflammatory CNS diseases

    Neurology

    (1999)
  • G.Z. Feuerstein et al.

    The role of cytokines in the neuropathology of stroke and neurotrauma

    Neuroimmunomodulation

    (1998)
  • W.H. Fischer et al.

    Regulation of IL-6 synthesis in human peripheral blood mononuclear cells by C3a and C3a(desArg)

    J. Immunol.

    (1999)
  • J.M. Galasso et al.

    Inhibition of TNF-alpha can attenuate or exacerbate excitotoxic injury in neonatal rat brain

    NeuroReport

    (2000)
  • Cited by (0)

    View full text