ReviewClosed head injury—an inflammatory disease?
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
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