IL-18: a key player in neuroinflammation and neurodegeneration?

Review

TRENDS in Neurosciences Vol.28 No.9 September 2005

IL-18: a key player in neuroinflammation and neurodegeneration? Ursula Felderhoff-Mueser1, Oliver I. Schmidt2, Andreas Oberholzer2, Christoph Bu¨hrer1,3 and Philip F. Stahel2 1

Department of Neonatology, Campus Virchow Klinikum, Charite´ University Medical School, 13353 Berlin, Germany Department of Trauma and Reconstructive Surgery, Campus Benjamin Franklin, Charite´ University Medical School, 12200 Berlin, Germany 3 University Children’s Hospital, 4005 Basel, Switzerland 2

Corresponding author: Stahel, P.F. ([email protected]). Available online 14 July 2005

Inflammatory stimuli

IL-18 gene

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Introduction Cytokines are crucial mediators of neuroinflammation and acute and chronic neurodegeneration in various pathological conditions in the CNS [1–4]. Their involvement in CNS disease represents a rapidly evolving area of neuroscience research. Among the candidate molecules, interferon (IFN)-g, tumor necrosis factor (TNF)-a, lymphotoxin (LT)-a (formerly TNF-b) and the interleukins (IL)-1, IL-6, IL-8, IL-12 and IL-23 are important mediators of neuroinflammation under various conditions of neuropathology [5–9]. These include acute insults due to head injury, stroke, intracranial hemorrhage, perinatal hypoxia or iatrogenic perinatal hyperoxia, in addition to chronic autoimmune and neurodegenerative conditions such as Alzheimer’s disease, multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE; the animal model for MS) [2,5–9]. For several years, a detrimental function has been attributed to cytokine-mediated neuroinflammation, owing to its association with neuronal cell death and adverse outcome. However, the controversial concept of a ‘dual role’ of cytokines in the CNS has emerged in recent years, based on experiments demonstrating both neurotoxic and neuroprotective functions for these inflammatory mediators, depending on the kinetics

of their regulation and expression in the injured brain [2,10–12]. IL-18, previously termed IFN-g-inducing factor, is a member of the IL-1 family of pro-inflammatory cytokines. It is synthesized as an inactive 24-kDa precursor protein (pro-IL-18) that is subsequently processed by caspase-1 into its mature and biologically active form, which has a molecular weight of 18 kDa [13,14]. The secreted proIL-18 can also be processed into its active form by various extracellular enzymes constitutively expressed by leukocytes, such as proteinase-3 [14,15] (Figure 1). The active form of IL-18 induces signal transduction by binding to its heterocomplex IL-18a/b receptor expressed on diverse celltypes [13,14,16]. These include cells resident in the CNS, such as hypothalamic neurons and murine glia [17,18]. Functional IL-18 receptor (IL-18R) expression on neurons and glia was demonstrated by stimulation experiments, in vitro using primary murine cell cultures and ex vivo using murine hippocampal slices [19,20]. More specifically, IL-18-mediated signal transduction pathways were shown to be activated in murine microglial cultures [19], and IL-18 enhanced both synaptic glutamate release and

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Interleukin (IL)-18 is a potent inflammatory cytokine of the IL-1 family. It is synthesized as an inactive precursor (pro-IL-18), which is cleaved into its functionally active form by caspase-1. Resident cells of the CNS express IL-18 and caspase-1 constitutively, thus providing a local IL-18-dependent immune response. Recent studies have highlighted a crucial role for IL-18 in mediating neuroinflammation and neurodegeneration in the CNS under pathological conditions, such as bacterial and viral infection, autoimmune demyelinating disease, and hypoxic–ischemic, hyperoxic and traumatic brain injuries. This review provides a synopsis of the current knowledge of IL-18-dependent mechanisms of action during acute neurodegeneration in immature and adult brains.

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Figure 1. IL-18 activation pathways. Pro-inflammatory stimuli induce expression of the inactive precursor protein pro-IL18. Upon activation of caspase-1 or caspase-1like enzymes, intracellular cleavage of pro-IL18 occurs, leading to formation of active IL-18 and secretion into the extracellular space. Alternatively, pro-IL-18 can be secreted into the extracellular space itself, where the enzyme proteinase-3 activates IL-18.

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postsynaptic AMPA receptor expression in murine hippocampal neurons [20]. Beyond the CNS, the biological effects of IL-18 binding to IL-18R include induction of Th1 and Th2 helper T-cell responses and of cytotoxic activity by natural killer cells, in addition to propagation of intrinsic and extrinsic pathways of apoptosis [14,16,21–23]. Based on recent experimental and clinical studies, IL-18 is also a presumed ‘key’ cytokine in the CNS, controlling two distinct immunological regulatory pathways of cytotoxic and inflammatory responses under neuropathological conditions (Figure 2). This review summarizes the present knowledge on the role and function of IL-18 in the CNS, with emphasis on the differences between neonatal (immature) and adult (mature) brains. The potential for pharmacological inhibition of intracerebral IL-18 activity is also discussed with regard to new strategies for attenuating neuroinflammation and neurodegeneration in CNS injury and disease. Role of IL-18 in the developing brain Although pro-inflammatory cytokines have been previously identified as important mediators of acute neurodegeneration [2], data on the role of IL-18 in the developing brain are limited [24]. Prinz and co-workers were the first to study the constitutive and inducible

expression of IL-18 and related signaling events in microglial cultures from newborn mice and by immunoprecipitation in brain homogenates of mice aged 6, 20 and 63 days [19]. IL-18 was preferentially expressed during early postnatal stages and subsequently downregulated, being virtually absent in the brains of adult mice, suggesting an IL-18-dependent role in brain maturation processes [19]. Only few studies have addressed the context of IL-18-mediated injury to the immature CNS. In the Rice–Vannucci neonatal rodent model of a moderate hypoxic-ischemic injury, Hedtja¨rn and co-workers found distinct upregulation of IL-18 on microglia, and this colocalized with caspase-1 and IL-1b [25]. The post-injury infarction area, extent of subcortical white matter injury and neuropathological scores were significantly decreased in neonatal IL-18K/K mice, suggesting that IL-18 could be functionally involved in exacerbating hypoxic injury to the neonatal brain [25,26]. In a different developmental brain- injury model, exposure to supraphysiological oxygen concentrations caused widespread apoptotic cell death in various regions of the immature brain [27]. Intracerebral gene and protein levels of caspase-1, IL-1b, IL-18 and IL-18R were upregulated within a few hours of exposure to oxygen. Moreover, IL-18 and IL-18R immunoreactivity was detected on immature neurons in apoptotic brain areas, suggesting a possible role in

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Figure 2. Working hypothesis for the dual roles of IL-18 in mediating neuroinflammation and neurodegeneration. Microglia are the major source of IL-18, which enhances microglial caspase-1 expression in an autocrine and paracrine fashion (known as the IL-18 forward loop). Furthermore, IL-18 induces microglial production of matrix metalloproteinase (MMPs) and other pro-inflammatory cytokines, such as TNF and IL-1b. Extravasation of polymorphonuclear leukocytes (PMNs) and monocytes/macrophages is amplified by IL-18-dependent upregulation of intercellular adhesion molecule-1 (ICAM-1) on endothelial cells and by microglial production of chemokines of the CXC- and CC-family, such as CXCL-8 (IL-8) and CCL-3 (MIP-1a). IL-18 induces the respiratory burst and degranulation of PMNs, which leads to local release of neurotoxic enzymes. Upon stimulation with IFN-g secreted by monocytes, microglia and PMNs release reactive oxygen species (ROS), which further contribute to neuroinflammation and cytotoxicity. In addition, microglia, oligodendroglia and astrocytes express FasL, which is induced by IL-18, thereby increasing the occurrence of Fas-mediated neuronal apoptotic cell death under inflammatory conditions. www.sciencedirect.com

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IL-18-induced neuronal cell death [28]. In these studies, genetic deletion of IL-1 receptor-associated kinase 4 (IRAK-4), which is pivotal for both IL-1b and IL-18 signal transduction, resulted in protection against oxygen-

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mediated neurotoxicity. This indicates that both caspase1-dependent interleukins (IL-1b and IL-18) make a crucial contribution to hyperoxia-induced apoptotic damage in the immature CNS [28].

Table 1. Role of IL-18 in neuropathology: clinical and experimental dataa Neuropathology (model and/or disease) EAE

Species

IL-18 levels in the brain

Effects of IL-18

Refs

Lewis rats

ND

[41]

EAE

Lewis rats

Increased IL-18 mRNA in EAE spinal cord Increased IL-18 mRNA in EAE brains

[35]

Experimental dopaminergic neurodegeneration

IL-18K/K mice (C57BL/6 strain)

Increased microglial IL-18 in substantia nigra

Bacterial meningitis, viral meningoencephalitis, MS

Human

MS

Human

ND

[39]

VSV encephalitis

BALB/c mice

IL-18 does not have a role in the host response to VSV encephalitis

[55]

HIV-associated opportunistic brain infection

Human

Increased IL-18 levels in CSF of bacterial meningitis patients (less in viral infection and MS) Elevated IL-18 and receptor protein expression in active MS lesions Constitutive IL-18 and caspase-1 mRNA expression in murine brains; no effect of exogenous IL-18 administration Elevated IL-18 levels in CSF of HIVC patients with cerebral infections

Neutralizing anti-IL-18 antibodies block the development of EAE Reduced susceptibility to dopaminergic neuronal loss and reduced microglial activation in IL-18K/K mice ND

[67]

Influenza A virus encephalitis

IL-18K/K mice (C57BL/6 strain)

Enhanced IL-18 production by microglia in infected brains

Pneumococcal meningitis

IL-18K/K mice (C57BL/6 strain)

Cryptococcal meningoencephalitis Ischemic stroke (permanent MCAO model)

BALB/c mice

ND

[49]

Ischemic stroke (temporary MCAO model) Ischemic stroke

IL-18K/K mice (C57BL/6 strain) Human

Upregulation of IL-18 protein and mRNA expression in infected brain tissue Increased IL-18 gene expression in infected brains Increased delayed intracerebral IL-18 and caspase-1 mRNA expression in injured brain No significant changes of IL-18 in the early phase after stroke Elevated IL-18 serum levels

Correlation between intrathecal IL-18 levels and development of opportunistic brain infection in HIVC patients Protective effect of IL-18 by enhanced clearance of neurovirulent Influenza A infection Prolonged survival and reduced neuroinflammation in IL-18K/K mice ND

No effect in IL-18K/K mice

[50] [51]

Axonal injury (optic nerve and sciatic nerve)

Wistar rats

IL-18 levels in serum are predictive of outcome ND

Closed head injury Closed head injury

Human C57BL/6 mice

[53,54] [53]

Closed head injury

C57BL/6 mice

Neonatal hypoxia-ischemia (Rice–Vannucci model)

IL-18K/K mice (C57BL/6 strain), Wistar rats

Periventricular leukomalacia in preterm infants

Human

Intra-amniotic inflammatory response

Human

ND Inhibition by IL-18BP is neuroprotective TNF inhibits intracerebral IL-18 Reduced infarct volume and neuropathology score in IL-18K/K mice. IL-18 contributes to white matter injury in neonatal brain Elevated IL-18 levels are associated with adverse neurological outcome IL-18 contributes to neonatal brain injury

Neonatal hyperoxia

Wistar rats, IRAK-4 K/K mice (C57BL/6 strain)

Reduced apoptosis in IRAK-4 K/K mice, inhibition by IL-18BP is neuroprotective

[28]

a

Wistar rats

Enhanced IL-18 expression on infiltrating macrophages after nerve crush injury Elevated IL-18 protein levels in CSF Elevated IL-18 protein levels in brain homogenates Elevated IL-18 protein levels in brain homogenates Elevated IL-18, IL-18R, IL-1b and caspase-1 protein and mRNA expression in the injured brain

Elevated IL-18 protein levels in cord blood of preterm infants correlated with adverse neurological outcome IL-18 levels in umbilical blood correlate with white matter injury and cerebral palsy in preterm infants IL-1b, IL-18, IL-18R and caspase-1 protein and mRNA expression on microglia and neurons

[40]

[38]

[58]

[60]

[61]

[52]

[54] [25,26]

[68]

[24]

Abbreviations: CSF, cerebrospinal fluid; EAE, experimental autoimmune meningoencephalitis; IL-18BP, IL-18-binding protein; IRAK-4, interleukin-1 receptor-associated kinase-4; MCAO, middle cerebral artery occlusion; MS, multiple sclerosis; ND, not determined; TNF, tumor necrosis factor; VSV, vesicular stomatitis virus.

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Pathobiology of IL-18 in the adult brain: double trouble? In the rodent brain, IL-18, its receptor and caspase-1 are constitutively expressed by astrocytes, microglia, neurons and ependymal cells [17,19,20,29–32]. Binding of IL-18 to its receptor expressed on resident and infiltrating cells in the CNS leads to activation of the transcription factor NFkB via a complex intracellular signaling cascade [14,19,33,34]. Thus, functional maturation and activation of IL-18 can occur in the brain under inflammatory conditions [18]. Experimental and clinical studies suggested a crucial role for IL-18-mediated neuroinflammation and neurodegeneration (Table 1). This double effect of IL-18 in the brain is highlighted here with regard to its role in autoimmune, ischemic, traumatic and infectious disorders of the CNS. Autoimmune and dopaminergic neurodegeneration The potential contribution of IL-18 and caspase-1 to acute and chronic neurodegeneration has been extensively investigated in MS patients and in models of EAE and dopaminergic neurodegeneration [35–40]. Early data from a model of EAE in Lewis rats revealed increased expression of the genes encoding IL-18 and caspase-1 in the CNS during acute stage of disease [41]. Furthermore, expression of both IL-18 and caspase-1 mRNA increased in nerve roots during active disease progression of experimental autoimmune neuritis, a model of inflammatory demyelinating polyneuropathy in rats [42]. In the experimental setting of EAE, the importance of IL-18 in generation of Th1 responses has been validated by a significant attenuation of disease after administration of neutralizing anti-IL-18 antibodies [35]. Similarly, the neuropathological sequelae of EAE were attenuated either by pharmacological inhibition of caspase-1 or in genetically engineered caspase-1K/K mice [37], implicating the IL-18–caspase-1 pathway as crucial in amplifying Th1dependent immune responses under neurodegenerative conditions in the CNS. This notion was supported by recent findings of resistance to EAE in IL-18-deficient mice, whereas administration of recombinant IL-18 enhanced the severity of EAE in wild-type mice and restored the ability to generate Th1 immune responses in the IL-18-null mice [43]. These studies demonstrated that IL-18 can direct autoreactive T cells and promote autoimmune neurodegeneration in the CNS via induction of IFN-g by natural killer cells [43]. In the clinical setting, caspase-1 levels in peripheral blood mononuclear cells were found to be higher in MS patients than in healthy controls [36,37]. In this study, caspase-1 gene expression levels in isolated monocytes correlated with MS disease activity, as determined by cerebral magnetic resonance imaging (MRI) lesions [36,37]. Fassbender and colleagues were the first to analyze IL-18 levels in cerebrospinal fluid (CSF) of patients with MS, bacterial meningitis and viral meningoencephalitis [38]. In this study, 94% of patients with bacterial meningitis and 43% of those with viral infections had increased IL-18 protein levels, whereas only 3% of MS patients had detectable IL-18 levels in the intrathecal compartment [38]. By contrast, Balashov and co-workers reported increased local expression of IL-18 and IFN-g in www.sciencedirect.com

demyelinating cerebral lesions of MS patients, suggesting that CSF levels do not accurately reflect the local tissue expression of these mediators in autoimmune CNS disease [44]. This hypothesis is corroborated by a more recent study of patients suffering from the relapsing–remitting form of MS, where individuals with acute exacerbations and active gadolinium-enhancing lesions in MRI had significantly greater IL-18 levels in serum and CSF than did MS patients without positive MRI lesions or control patients without neurological disease [45]. In agreement with these observations, Cannella and Raine reported that expression of IL-18 and its receptor on oligodendrocytes was greater in brain tissue from patients with active MS than in brain sections from patients with silent MS or from neuropathologically normal subjects [39]. Together, these findings implicate IL-18 as an important player in the inflammatory pathogenesis of active autoimmune CNS diseases [39,45]. Neuroinflammation in brain injury and infection Neuroinflammation is crucial in exacerbation of hypoxic– ischemic and traumatic brain injury, exacerbation of brain infection, and development of secondary cerebral insults [2,3,14,46–48]. IL-18 has been involved in the induction and progression of ischemia-induced inflammation in experimental models of middle cerebral artery occlusion (MCAO). As such, focal ischemic brain injury in rats has been shown to induce delayed IL-18 and caspase-1 expression in microglia and monocytes/macrophages in the infarcted cortex [49]. Interestingly, the expression profile of caspase-1 paralleled the increase of IL-18 levels, but not that of IL-1b levels, suggesting temporal diversity of expression within IL-1-family cytokines and implicating the IL-18–caspase-1 pathway in late-stage neuroinflammatory responses to focal cerebral ischemia [49]. The observed lack of IL-18 induction in the early phase (24 h) following stroke in rat brains [49] was confirmed by recent findings from a model of temporary MCAO in IL-18K/K mice [50]. In this study, intracerebral IL-18 levels were not significantly altered in the first 24 h after stroke in C57BL/6 wild-type mice, and the genetic deficiency of IL-18 did not affect post-ischemic infarct volumes [50]. Thus, the data from MCAO models in mice and rats implies that IL-18 does not contribute to neuropathology within the first 24 h after stroke [49,50]. For correct interpretation and comparison of the data from these two studies on experimental MCAO, the differences in species (rats versus mice), in experimental modalities (permanent occlusion versus temporary ischemia with reperfusion) and in time-points assessed (late-stage versus first 24 h) should be taken into account [49,50]. Viewing these data together, it appears that IL-1 contributes to early neurodegeneration, whereas IL-18 mediates delayed neuroinflammatory events after hypoxic–ischemic brain injury [2,49,50]. In stroke patients, elevated IL-18 levels in serum were shown to correlate both with the extent of hypodense area volumes in craniocerebral computed tomography (CT) scans and with functional disability [51]. Moreover, serum IL-18 levels were higher in patients with a non-lacunar stroke subtype than in those with lacunar types of

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stroke [51]. Thus, it appears that IL-18 is involved in stroke-induced neuroinflammation and that the quantification of initial serum IL-18 levels could be helpful in predicting the outcome after cerebral ischemia [51]. Similar to the role in hypoxic–ischemic cerebral insults, IL-18 also seems to be a key player in the pathology of traumatic brain injury [46,52–54]. Menge and co-workers reported first evidence of upregulated IL-18 gene and protein expression following optic and sciatic nerve crush injury in a rat model [52]. In these studies, the constitutive levels of IL-18 mRNA expression were higher in the CNS (optic nerve) than in peripheral nerve tissue (sciatic nerve), as determined by RT–PCR analyses of neural rat specimens [52]. After experimental axonal crush injury, IL-18 expression dramatically increased on both injured optic and injured sciatic nerves [52]. The cellular sources of increased IL-18 levels were determined mainly as infiltrating macrophages within the first days after axonal injury [52]. In addition, local resident microglia were shown to exhibit enhanced IL-18 expression mainly at sites of myelin degradation, suggesting an involvement of IL-18-mediated microglial neurotoxicity [52]. Thus, IL-18 seems to be involved in the cytokine network associated with the robust neuroinflammatory response after brain injury [11,46,52]. This notion was confirmed by clinical and experimental data from studies of severe closed head injury in humans and in a standardized weight-drop model in mice [53]. Yatsiv and colleagues reported significantly elevated IL-18 protein levels in daily CSF samples of patients with severe closed head injury for up to ten days after trauma, as compared with normal human CSF [53]. Notably, the peaks of intrathecal IL-18 levels in brain-injured patients were almost 200-fold higher than in CSF from control subjects without neuroinflammatory disease [53]. In addition, IL-18 protein expression was quantified in the murine CNS by ELISA of brain homogenates. Detectable constitutive IL-18 levels were reported in normal mouse brains [53,54], in accordance with previous data on constitutive expression in rat brains [17,29,31] and in the murine CNS [18,52,55]. Seven days after experimental closed head injury in mice, brain IL-18 protein levels were significantly higher than in the brains of normal and sham-operated mice [53]. This prolonged upregulation confirms previous findings of a delayed IL-18-mediated inflammatory response to brain injury [49,56]. Studies of in vitro cell cultures, of patients with meningitis or sepsis, and of experimental models of infectious CNS diseases have implicated IL-18 in the inflammatory response to endotoxin and to bacterial, viral and cryptococcal infections [18,19,30,33,38,55,57–61]. In models of pneumococcal and cryptococcal meningitis, IL-18 was shown to be upregulated in the infected brain and to contribute to the detrimental inflammatory response and secondary damage [60,61]. Induction of bacterial meningitis by Streptcoccus pneumoniae inoculation resulted in a significant intracerebral upregulation of IL-18 in mice [60]. Notably, IL-18K/K mice with pneumococcal meningitis displayed prolonged survival and a decreased neuroinflammatory response compared with infected wild-type littermates, suggesting that IL-18 www.sciencedirect.com

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contributes to the detrimental endogenous inflammatory response in bacterial meningitis [60]. These data were supported in a model of fungal infection of the CNS, where mice with Cryptococcus neoformans meningoencephalitis had increased IL-18 mRNA expression in the infected brain [61]. In models of viral CNS infection, IL-18 was shown to have a key role in activating microglial functions by inducing neuronal IFN-g release in brain parenchyma, and thus supporting the viral clearance of infected neurons [58]. In these studies, IL-18-gene-deficient mice had impaired elimination of influenza-A-infected neurons from the brain, compared with infected wild-type mice [58]. There seems to be a virus-specific response regarding IL-18-mediated mechanisms of viral clearance, because the beneficial neuroprotective effects of IL-18 seen in neurovirulent influenza-A infection [58] were not observed in a model of viral CNS infection by vesicular stomatitis virus [55]. Thus, IL-18-mediated events in the infected or injured adult brain seem to range from detrimental effects (by exacerbating intracranial inflammation and inducing secondary brain injuries, as shown for stroke, trauma, meningitis and autoimmune encephalomyelitis) to neuroprotection (by supporting IFN-g-mediated clearance of pathogens in models of viral infection). IL-18BP: an antagonist with pharmacological potential? Several functional antagonists and inhibitors of IL-18 neutralize its pro-inflammatory effects [14,54,62]. The most important naturally occurring antagonist is IL-18binding protein (IL-18BP), a secreted protein that displays high-affinity binding to mature IL-18 but not to pro-IL-18 [63–65]. Four distinct isotypes of human IL-18BP and two isotypes of murine IL-18BP derive from alternative splicing of the respective genes; two of the human isotypes and both murine isotypes function biologically by neutralizing IL-18 [66]. Constitutive IL-18BP gene expression in the CNS has been demonstrated on primary murine microglial and mixed glial cultures in vitro [18], and in normal rat brains in vivo [17]. In studies of experimental head injury, systemic administration of recombinant IL-18BP one hour after trauma resulted within seven days in significantly improved neurological recovery, which was associated with IL-18BP-dependent downregulation of intracerebral IL-18 levels [53]. Furthermore, hyperoxia-induced brain injury was largely attenuated by administration of recombinant IL-18BP [28]. Based on these findings, targeting IL-18 could have therapeutic potential in the treatment of injuries to the immature and adult brain. Concluding remarks Despite thorough insights into the mechanisms of IL-18mediated neuroinflammation in CNS injury and disease, the exact role of IL-18 in terms of beneficial effects (as in viral infection) or detrimental effects (as in traumatic or neonatal brain injury) remains to be clarified (Box 1). Pharmacological targeting of IL-18-mediated mechanisms of action in acute neurodegeneration and neuroinflammation (e.g. by post-insult administration of recombinant IL-18BP) could be of therapeutic value for ameliorating

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Box 1. Unanswered questions † How are expression of IL-18 and its receptor in the brain, and IL-18-dependent signal transduction pathways, regulated under in vivo neuroinflammatory conditions? † Do the caspase-1-processed cytokines IL-1b and IL-18 have synergistic or antagonistic mechanisms with regards to action kinetics in the in the inflamed brain? † Are some of the neuroinflammatory events attributed to IL-18 in the CNS caused indirectly, by IL-18-mediated induction of IFN-g in immune cells? Direct effects of IL-18 on acute neurodegeneration, and indirect effects involving IL-18-induced IFN-g on autoimmune disease, need to be further elucidated in experimental models of neuropathology. † hat are the kinetics of blood–brain barrier dysfunction in experimental models and in patients with neuroinflammatory diseases, with regard to the ‘time-window of opportunity’ for systemic administration of IL-18 antagonists such as IL-18BP? Which intrathecal levels of IL-18BP can be achieved by systemic administration? † Are there any beneficial effects of intracerebral IL-18 expression (e.g. in terms of promoting delayed neuroregenerative mechanisms)? † Should a therapeutic approach (e.g. by IL-18BP administration) therefore incorporate a temporal limitation, to allow (potentially beneficial) intracerebral IL-18 activity at defined time-points?

secondary brain-injury patterns, and thus provides a strong rationale for future studies in other models of injury to neonatal and adult brains. Acknowledgements We thank Mrs Anette Sommer for professional assistance with the illustration in Figure 2. U.F. is supported by a grant from the Sonnenfeld Stiftung (No. 1999.091.1). C.B. and U.F. are supported by a grant from the BMBF (01ZZ0101). P.F.S., O.I.S. and A.O. are supported by grants from the German Research Foundation (DFG, No. STA 635/1–1, STA 635/1–2, STA 635/2–1, TR 742/1–1, OB 181/1–1).

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