Mechanisms of regulation for interleukin-1β in neurodegenerative disease

Neuropharmacology 52 (2007) 1563e1569 www.elsevier.com/locate/neuropharm

Mini-review

Mechanisms of regulation for interleukin-1b in neurodegenerative disease Anastasia Simi, Dominique Lerouet, Emmanuel Pinteaux, David Brough* Faculty of Life Sciences, C.2210 Michael Smith Building, University of Manchester, Manchester M13 9PT, UK Received 9 January 2007; received in revised form 27 February 2007; accepted 28 February 2007

Abstract The interleukin-1 family of cytokines are central to the pathology of acute and chronic diseases of the central nervous system. We describe current evidence on the transcriptional and post-transcriptional regulation of interleukin-1b production, secretion and activity in the brain. Regarding the induction of protein synthesis, the possible involvement of Toll like receptor-4 is discussed including evidence that ischemic brain damage is reduced in Toll like receptor-4 knockout mice. The post-translational involvement of the P2X7-receptor and caspase-1 in the processing and release of active IL-1b is also considered, as is evidence suggesting a possible extracellular cleavage of pro-IL-1b by neutrophil derived proteases. We provide some fresh perspectives on how interleukin-1b may be regulated and how these mechanisms could be targeted in disease. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Interleukin-1b; Caspase-1; Inflammasome; Cerebral ischemia; P2X7-receptor; TLR4

1. Interleukin-1b and neurodegeneration Interleukin-1 (IL-1) represents a family of proteins critical in orchestrating immune and inflammatory responses to injury and infections. The most extensively characterised members of the IL-1 family are the agonist proteins IL-1a and IL-1b that exert their actions through the type I IL-1 receptor (IL-1RI). The family also contains an endogenous IL-1 receptor antagonist (IL1RA) that inhibits IL-1 actions mediated by IL-1RI. Of the two agonist proteins, IL-1b is the major secretory form and is reported to have neurotoxic actions (Allan and Rothwell, 2001). A wealth of experimental evidence supports a role for IL-1b in both acute and chronic neurodegenerative disease and is well documented and reviewed elsewhere (Lucas et al., 2006). 2. Mechanisms of IL-1b production in the injured brain IL-1b, in common with other inflammatory mediators, is expressed at very low levels and has no overt neurotoxic effect * Corresponding author. Tel.: þ44 (0)161 275 5745; fax: þ44 161 275 5948. E-mail address: [email protected] (D. Brough). 0028-3908/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2007.02.011

when administered to a healthy brain as measured using vital dye histology (Lawrence et al., 1998). However, in response to injury, its expression is rapidly upregulated, and levels remain elevated for several days making it an attractive therapeutic target (Allan and Rothwell, 2001). Fig. 1 provides a schematic representation of the mechanisms of IL-1b generation and secretion described below. IL-1b biosynthesis is complex and is regulated at multiple levels. Most information on the mechanisms of IL-1b production derives from in vitro studies using peripheral cells, mainly monocytes and macrophages, and concerns IL-1b biosynthesis downstream of Toll like receptor-4 (TLR4) after bacterial lipopolysaccharide (LPS) stimulation. From studies carried out on microglia it seems that LPS-induced IL-1b production is dependent largely on NF-kB, but MAPK pathways and particularly p38 MAPK also play a role (Simi et al., 2002; Kim et al., 2004). Other stimuli related to neuronal injury, such as b-amyloid and S100B, are reported to employ the ERK and JNK pathways additional to p38 MAPK for microglial IL-1b production (Kim et al., 2004). Exposure of cultured rat microglia to a hypoxic insult results in the p38 MAPK-dependent upregulation of caspase-11, an enzyme upstream of caspase-1 activation and IL-1b secretion (Kim et al., 2003), and hypoxia inducible

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LPS/ endogenous ligands

Aditional activators

P2X7

TLR4 NALP3 ASC NF B

p38MAPK

Other NALPS/ adaptors

Microvesicle shedding/ Lysosome exocytosis/ Transmembrane exit

Caspase-1

IL-1

Pro-IL-1

Extracellular protease

? IL-1B

Pro-IL-1

Fig. 1. A schematic diagram summarising the currently known mechanisms involved in the generation and release of bioactive IL-1b.

Acute necrosis and disruption of the blood-brain-barrier (BBB) during brain injury will result in the release of factors that had previously remained intracellular or peripheral, and thus not present in a healthy brain. Such factors will become present in the interstitial fluid, subject to microglial surveillance and may promote microglial activation. Notably many of these factors such as gangliosides (Jou et al., 2006), small heat-shock proteins (Kakimura et al., 2002) and the extradomain A of fibronectin (Okamura et al., 2001) may be endogenous ligands for TLR4. However, a caveat to studies using recombinant ligands is the possible effects of low levels of endotoxin contamination (Tsan and Gao, 2004). Interestingly, TLR4 KO mice exhibit smaller infarcts in response to transient cerebral ischemia (Fig. 2) and myocardial ischemia (Oyama et al., 2004), and activation of the TLR4 pathway is required for the inflammatory response during ischemia-reperfusion injury in the liver (Zhai et al., 2004). In addition, the inflammatory response following spinal nerve transection is reduced in TLR4 KO mice (Tanga et al., 2005), supporting our observations (Fig. 2). Thus, it is Infarct volume (mm3)

factor-1 (HIF-1) can regulate IL-1b expression in cultured human and mouse astrocytes (Zhang et al., 2006). Downstream of these pathways, transcriptional activation of the IL-1B gene by NF-kB, AP-1, CREB, NF-IL-6 and SP-1 transcription factors can also occur (for review see Watkins et al., 1999). Additional mechanisms of control may include mRNA stabilisation through an LPS-responsive 30 -UTR element on the IL-1B gene (Kern et al., 1997) and a mechanism which may involve the p38 MAPK pathway and its downstream target MAPKAP-K2 (MK2) (Young et al., 1993; Kotlyarov et al., 1999). Far less information is available on the mechanisms of IL-1b production in response to brain injury in vivo. Resident and infiltrating immune cells produce IL-1b after brain injury. The main source of IL-1b in the brain following an acute injury are believed to be activated microglia, although astrocytes and infiltrating macrophages contribute to IL-1b production at times when the injury appears complete (Pearson et al., 1999; Mabuchi et al., 2000). Acute neuronal injury caused by hypoxia/ischemia, haemorrhage and seizures, or accumulation of extracellular fragments of b-amyloid all activate microglia and increase the production of IL-1b. However, it is not known if NF-kB or MAPKs are involved, and if IL-1b production is downstream of TLR4 activation. Although no study to-date has addressed these issues directly, there is some evidence to suggest these mechanisms could be involved. Activation of p38 MAPK is observed within astrocytes in the ischemic lesion of rats in response to cerebral ischemia (Irving et al., 2000) and in hippocampal microglia in response to global forebrain ischemia (Walton et al., 1998). Inhibitors of p38 MAPK are neuroprotective, and decrease concentrations of IL-1b and TNF-a in the brain after cerebral ischemia in rats (Barone et al., 2001). MK2 KO mice exhibit significantly reduced tissue levels of IL-1b and are also protected from ischemic injury (Wang et al., 2002). In addition to cerebral ischemia, p38 MAPK activity is observed in microglia expressing IL-1b following activation by injection of pre-aggregated b-amyloid in the rat brain (Giovannini et al., 2002).

60 WT (n=12)

50 40

TLR4 KO (n=9)

*

30

*

20 10 0

Total

Cortex

Striatum

Thalamus

Hippocampus

Fig. 2. Experimental stroke injury was induced by temporary occlusion of the Middle Cerebral Artery (MCAo, 45 min) in TLR4 KO mice and their WT counterparts. A total of 24 h after MCAo the brains were removed and frozen. Serial coronal brain sections were taken followed by cresyl violet staining and infarct volume calculation as described previously (Boutin et al., 2001). Total, cortical, striatal, thalamic and hippocampal damage was quantified. Open bars represent the WT group and closed bars the KO. The number of animals in each experimental group is indicated in parenthesis in the figure. Data are presented as infarct volume (mm3) and shown as the mean  SEM. *p < 0.05 KO vs. WT (Student’s t-test).

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plausible that the TLR4 pathway is responsible, at least in part, for IL-1b production in the injured CNS although this has yet to be formally demonstrated. Other receptors, or non-receptor mediated mechanisms, could of course contribute. Indeed, proteins of the NF-kB and MAPK pathways are redox-sensitive and can be directly activated by reactive oxygen species in rats after cerebral ischemia (Collino et al., 2006) or by increased levels of disease-associated proteins such as S100B, which is a potent pro-oxidant (Esposito et al., 2006). 3. P2X7-receptor expression and activation on microglia Macrophages and microglia synthesise pro-IL-1b in response to TLR4-receptor activation by LPS. These activated cells are thus ‘primed’ for a secondary stimulus that will result in maturation of the inactive pro-IL-1b, and secretion of an active IL-1b molecule. The notable exception to this rule is freshly isolated monocytes, where LPS alone is sufficient to promote processing and release of IL-1b (Perregaux et al., 1996). Processing of pro- to mature IL-1b depends on cleavage by the protease caspase-1 (Thornberry et al., 1992), although numerous other proteases, common to inflammatory exudates, can cleave pro-IL-1b to yield biologically active IL-1b molecules (Black et al., 1988; Irmler et al., 1995; Schonbeck et al., 1998; Coeshott et al., 1999). The stimulus most reported to promote processing and release of IL-1b is activation of the cell surface P2X7 receptor, commonly with the purine nucleotide ATP (Solle et al., 2001), but also by the neutrophil cathelicidin-derived anti-microbial peptide LL37 (Elssner et al., 2004), and by ADP-ribosylation (Seman et al., 2003). In the brain, the P2X7 receptor is expressed exclusively by microglia (Sim et al., 2004), and its expression is upregulated after acute brain injury such as cerebral ischemia (Melani et al., 2006), or in chronic CNS disease such as Alzheimer’s disease (Parvathenani et al., 2003; McLarnon et al., 2006). As discussed above, microglia are thought to provide a source of IL-1b in the brain during acute and chronic inflammatory brain diseases, and this has prompted researchers to investigate an involvement of the P2X7 receptor in the regulation of microglial IL-1b release (Ferrari et al., 1997b; Brough et al., 2002; Chakfe et al., 2002; Le Feuvre et al., 2003). In vitro, the application of high (mM) concentrations of ATP, required to activate the P2X7 receptor (North and Surprenant, 2000), to LPS-primed microglia results in the caspase-1-dependent processing and release of IL-1b (Ferrari et al., 1997b; Brough et al., 2002). It is not clear however, if this process is active in the brain after injury. Extracellular ATP concentrations, measured by microdialysis in rats, are reported to increase following cerebral ischemia (Melani et al., 2005), although not to the concentrations required to activate the P2X7 receptor and stimulate IL-1b secretion in vitro. It is known however, that changes in the ionic composition of the extracellular media can dramatically change the sensitivity of the P2X7 receptor for ATP (Perregaux and Gabel, 1998a; Virginio et al., 1999), and such changes in ionic balance may occur in an ischemic brain. Primary cultures of microglia isolated from P2X7 KO mice do not release IL-1b in response to ATP (Brough et al.,

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2002). However, there is no difference in lesion size after cerebral ischemia between wild-type (WT) and P2X7 KO mice (Le Feuvre et al., 2002a,b). In addition, IL-1RA, the naturally occurring IL-1RI antagonist, is neuroprotective in P2X7 KO mice exposed to cerebral ischemia (Le Feuvre et al., 2003). Administration of the P2X7-receptor agonist, BzATP, or of the antagonists, oATP and PPADS to the brain, fail to modify damage caused by cerebral ischemia in WT mice (Le Feuvre et al., 2003). In addition, excitotoxic damage in the rat, caused by striatal infusion of methano-glutamate, is unaffected by coadministration of PPADS or of another P2X7-receptor antagonist, KN-62 (Le Feuvre et al., 2003). Together, these results suggest that the P2X7 receptor is not important for IL-1b release in acute brain injury. However, peripheral administration of the non-selective purinergic receptor antagonist reactive blue 2, reduced lesion size caused by cerebral ischemia in rats, which the authors attribute to an inhibition of P2X7receptor function (Melani et al., 2006). Despite this report, our evidence suggests that the role of P2X7-receptor-induced IL-1b release following brain injury needs to be reconsidered. 4. Activation of caspase-1 Caspase-1 was originally termed ‘interleukin-1 converting enzyme’ (ICE) due to its ability to process pro- to mature IL-1b (Thornberry et al., 1992). P2X7-receptor activation of LPS-primed, primary, murine macrophages activates caspase-1 which, in addition to the release of IL-1b, results in a caspase-1-dependent cell death (Le Feuvre et al., 2002a,b). However, there are reports that caspase-1-generated IL-1b is released in the absence of cell death (Grahames et al., 1999; Gudipaty et al., 2003; Pelegrin and Surprenant, 2006). Although the absence of cell death is reported from studies using cell lines rather than primary cultures, it does at least illustrate that IL-1b release is not due solely to cell lysis (see below). Caspase-1 is synthesised as an inactive 45 kDa precursor, consisting of p20 and p10 sub-units linked by a 2 kDa linker region and containing an 11 kDa pro-domain at its N-terminus. The quaternary structure of the active enzyme is a tetramer consisting of two p10 and p20 subunits (Wilson et al., 1994). Activation of caspase-1 occurs by recruitment to an assembly of adaptor molecules collectively termed the ‘inflammasome’ (Martinon et al., 2002). Different inflammasome assemblies form and activate caspase-1 depending upon the inflammatory stimulus, although the adaptor molecule apoptosis-associated speck-like protein (ASC) is required for caspase-1 activation in all models studied to-date (Ogura et al., 2006). The variation appears to depend on adaptors upstream of the caspase-1-ASC interaction, members of the NALP (NACHT-, LRR, PYDcontaining) family of proteins. Perhaps of particular interest is NALP3, also known as cryopyrin. In response to P2X7receptor-stimulation it is a NALP3-containing inflammasome that activates caspase-1 (Mariathasan et al., 2006). Although an involvement of NALP3 in caspase-1-mediated generation of IL-1b in the brain has yet to be formally demonstrated, ATP-induced IL-1b secretion from microglia could occur through a NALP3-containing inflammasome. Precisely how

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P2X7 receptor stimulation activates caspase-1 via NALP3 is unclear. Several studies have suggested that Kþ efflux following P2X7-receptor activation is essential for caspase-1 activation and IL-1b release (Perregaux and Gabel, 1994; Brough et al., 2003). However, recent evidence suggests Kþ efflux alone is not sufficient, but that it is important for the activation of a hemi-channel-, pannexin-1-dependent inflammasome, a recently described effector of caspase-1 activation and IL-1b release (Pelegrin and Surprenant, 2006, 2007). As discussed, our data suggest that the P2X7 receptor is not a contributor in acute brain injury. However, there may be additional activators of NALP3 which is present in microglia. Although activation of caspase-1 via the inflammasome is reported to coincide with IL-1b processing and release, caspase-1 can influence processes in the brain independently of IL-1b. For example, inhibition of physiologically active caspase-1 potentiates non-toxic, AMPA-induced increases in cytosolic Ca2þ concentration, and long term potentiation (LTP) in hippocampal neurons (Lu et al., 2006). It is unclear how activation of caspase-1 is regulated under these circumstances. 5. Mechanism of IL-1b secretion Despite numerous proposals, there is still controversy over how IL-1b makes its cellular exit. IL-1b is a leaderless protein and does not harness the classical ER-Golgi route of protein secretion (Rubartelli et al., 1990). Early investigations reported cell lysis as a mechanism of IL-1b secretion from LPS-treated monocytes, as it correlated with increased levels of the cytosolic enzyme lactate dehydrogenase (LDH) in the supernatant (Hogquist et al., 1991). Indeed, in primary cultures of murine macrophages, activation of caspase-1 after P2X7receptor stimulation causes a caspase-1-dependent cell death (Le Feuvre et al., 2002a,b). Injection of ATP to the mouse peritoneal cavity, 2 h after LPS injection, caused cell death that correlated with increased IL-1b levels (Griffiths et al., 1995). However, cell lysis cannot solely account for the release of IL-1b in response to ATP. The appearance of mature IL-1b occurs prior to LDH in the supernatants of ATP-treated macrophages (Ferrari et al., 1997a; Perregaux and Gabel, 1998b), and as mentioned above, release of IL-1b from cell lines in the absence of cell death has been reported (Grahames et al., 1999; Gudipaty et al., 2003; Pelegrin and Surprenant, 2006). Thus, although it seems that under certain conditions, IL-1b is released from dying macrophages and microglia, the relevance of cell death to IL-1b release is not clear. In human monocytes, a fraction of cellular pro-IL-1b localizes to cathepsin D containing late endosomes and early lysosomes, as shown by electron microscopy and sub-cellular fractionation techniques. In addition, there is evidence that this fraction is released by the regulated secretion of these lysosomes (Andrei et al., 1999, 2004). However this may not account for the majority of cellular IL-1b release, and at least in macrophages, there appears to be other mechanisms involved (Brough and Rothwell, 2007). Shedding of microvesicles from the plasma membrane containing IL-1b has been reported in THP.1 monocytes and N9 microglial cells (MacKenzie et al.,

2001; Bianco et al., 2005). It appears that these two processes (lysosomal and microvesicle secretion) are unrelated and represent two distinct mechanisms of release. There is also the possibility that IL-1b is secreted directly across the plasma membrane (Singer et al., 1995; Brough and Rothwell, 2007), although no transport protein has been identified, the structural homologues IL-1a and FGF-1 can be secreted directly across the membrane by assuming a molten globule character and increasing their solubility in lipid membranes (Prudovsky et al., 2003). A little considered alternative is that secretion of pro-IL-1b could occur in the absence of intracellular caspase-1 activity. In response to LPS, primary cultured rat microglia secrete large amounts of pro-IL-1b (Chauvet et al., 2001). When compared, there is a striking difference in the secretion of IL-1b between microglia and peripheral macrophages isolated from C57BL/6 mice. Stimulation by ATP of an LPS-primed macrophage results in the relatively rapid generation and secretion of 17 kDa IL-1b (Brough and Rothwell, 2007). No 17 kDa IL-1b is observed in the cell lysate of ATP-treated microglia, and the 17 kDa form only appears in the supernatant at later timepoints, where it represents the minority of secreted IL-1b, the pro-form being predominant (Brough et al., 2002). Pro-IL-1b can be cleaved by proteases in addition to caspase-1, several of which, such as elastase, granzyme A, matrix metalloprotease 9 (MMP9) and proteinase 3, are secreted by neutrophils recruited to sites of tissue damage (Black et al., 1988; Irmler et al., 1995; Schonbeck et al., 1998; Coeshott et al., 1999). This identifies the possibility that pro-IL-1b could be cleaved in the extracellular milieu at sites of tissue injury. This may be the case reported for a peripheral model of inflammation. Tissue damage caused by a subcutaneous injection of turpentine results in an identical systemic acute-phase response in WT and caspase-1 KO mice, although the response was completely abrogated in IL-1b KO mice (Fantuzzi et al., 1997). If we consider that the P2X7-receptor is important for processing and release of mature IL-1b in vivo then we can interpret the negative results from our P2X7 KO studies to suggest that, during brain injury, pro-IL-1b is processed extracellularly, either by proteases secreted from invading inflammatory cells such as neutrophils, or even by caspase-1 released by necrotic neurons. Although ischemic brain damage is reduced in caspase1 KO mice (Schielke et al., 1998) it should be considered that this may not necessarily be due to an influence on IL-1b, but may be an effect on neuronal excitability as discussed above. 6. Opportunities for therapeutic intervention Clinical studies modifying the IL-1 system in CNS disease are limited, although it is in clinical use for rheumatoid arthritis (RA) (Bresnihan, 2001). A randomised phase II clinical study of recombinant human IL-1RA in acute stroke patients suggested safety and some efficacy, particularly in patients with cortical infarcts (Emsley et al., 2005). It may however prove difficult to achieve sufficient IL-1 inhibition in humans, as 100e1000 fold local excess of IL-1RA is required to do so. Although preliminary evidence suggests IL-1RA may act both

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peripherally and within the CNS to modify acute brain injury, the ability of IL-1RA to cross the BBB, and its pharmacokinetic properties, are important issues to consider, which may be difficult to manipulate in a relatively large protein. Apart from agents aiming at neutralising IL-1 or the binding to its receptor (Anakinra; IL-1 trap), alternative strategies utilising small-molecule pharmacological approaches are continuously emerging. Pyridinyl imidazole compounds of the SB series (SmithKline Beecham), termed cytokine-suppressive anti-inflammatory drugs (CSAIDs), inhibit cytokine production by blocking p38 MAPK (Lee et al., 1994), and a new class of fungal diterpenes that inhibit IL-1b production from human monocytes have been described (Ichikawa et al., 2001a,b). However, targeting IL-1b production may prove challenging, as the mechanisms of IL-1b synthesis discussed earlier appear to be generic, and the molecules involved (NF-kB, p38 MAPK) are important for a variety of cellular functions. Should the involvement of TLR4 in brain injury and disease be corroborated, TLR4 receptor antagonists may prove useful. A variety of synthetic lipid A analogs have been synthesized over the past decade, and most recently E5564 provided effective LPS antagonism in animals and humans (Hawkins et al., 2004). As our understanding of how the IL-1 system is regulated grows, targeting IL-1b release appears increasingly attractive. Caspase-1 inhibitors and other inhibitors of IL-1 processing are currently under development, and some are in Phase II trials for the treatment of RA and psoriasis (Pralnacasan, Aventis) (Braddock and Quinn, 2004). Despite the fact that caspase-1 is not the only protease that can cleave IL-1b, and IL-1b processing is not the only action of caspase-1, Pralnacasan induced a non-significant trend towards improvement on the ARC20 scale in a study in RA patients (Braddock and Quinn, 2004), and inhibits joint destruction in murine models of collageninduced arthritis (Rudolphi et al., 2003). The CP series of diasylphonyl urea-based compounds (cytokine-release inhibitory drugs or CRIDs) developed by Pfizer also inhibit IL-1b release (Perregaux et al., 2001). One suggested mechanism for the effect of CRIDs on IL-1b release is the inhibition of IL-1b post-translational processing through an interaction with GSTomega 1-1 (Laliberte et al., 2003). However, lesion size was unaltered in GST-omega 1.1 KO mice subjected to cerebral ischemia, as compared to their WT counterparts (Lerouet and Rothwell, unpublished data), and CRIDs inhibit ATP-induced IL-1b release in macrophages isolated from GST-omega 1.1 KO mice (Brough and Rothwell, unpublished data). The adaptor molecules comprising the inflammasome provide additional therapeutic targets and may inspire the design of new antiinflammatory molecules (Hauff et al., 2005). Certainly, inhibition of IL-1b provides a great opportunity for intervention in CNS disease, but we need to understand more about the mechanisms of its release as well as the proteolytic processes that regulate its bioactivity for designing successful pharmacotherapies. References Allan, S.M., Rothwell, N.J., 2001. Cytokines and acute neurodegeneration. Nat. Rev. Neurosci. 2, 734e744.

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