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TOPICAL REVIEW |
1 Strathclyde Institute for Pharmacy & Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow, G4 0NR, UK
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Abstract |
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(Received 31 January 2007;
accepted after revision 8 March 2007;
first published online 8 March 2007)
Corresponding author T. Bushell: Strathclyde Institute for Pharmacy & Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow, G4 NR, UK. Email: trevor.bushell{at}strath.ac.uk
Inflammation and CNS disorders
Despite the CNS and the immune system formerly being thought of as separate entities, it is now well recognized that the communication between these two systems is a bidirectional process (Exton et al. 2001; Watkins & Maier, 2005). With the increased understanding of this interaction, it has now become clear that one of the fundamental defence mechanisms of the immune system, namely inflammation, is implicated to play a major role in certain CNS disorders. Indeed, the up-regulation of inflammatory cytokines, for example TNF-
, TNF-
, IL-1 and IL-6, are observed in acute CNS conditions such as brain trauma, as well as in chronic CNS diseases states, such as Alzheimer's disease, Parkinson's disease and multiple sclerosis (Campbell, 2004; Lucas et al. 2006). This increased expression of inflammatory cytokines in CNS disorders mirrors their well-documented role in peripheral inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease (McInnes & Gracie, 2004; Gordon et al. 2005). Significantly, identification of cytokines in peripheral diseases has led to the development of novel therapies for the treatment of these inflammatory disorders (Olsen & Stein, 2004; Panaccione et al. 2005). However, other common mediators in these inflammatory diseases have now been identified, including the G-protein coupled receptor (GPCR) proteinase-activated receptor-2 (PAR-2).
Proteinase-activated receptors
Proteinase-activated receptors (PARs) are a novel class of GPCRs that are unique in their activation, whereby the cleavage of the N-terminus by a serine proteinase unveils a sequence that acts as a ‘tethered-ligand’. The ‘tethered-ligand’ then binds to the second extracellular loop of the receptor, leading to the activation of the receptor (MacFarlane et al. 2001; Ossovskaya & Bunnet, 2004; Fig. 1). To date, four members of the PAR family have been cloned, namely PAR-1 to -4. Of these, PAR-1, -3 and -4 are preferentially activated by thrombin, whereas trypsin and trypsin-like proteinases are proposed to preferentially activate PAR-2 (MacFarlane et al. 2001; Ossovskaya & Bunnet, 2004). However, it should be noted that in astrocytes in which PAR-2 has been desensitized as well as in astrocytes derived from PAR-2 knockout mice, trypsin still elicits a robust, albeit reduced, increase in intracellular calcium (Ca2+) (Hamill 2006; T. Bushell et al. unpublished data), indicating that trypsin can act on multiple receptors. Several selective PAR-activating peptides (APs), based on the tethered ligand sequence for each receptor, e.g. TFLLR-NH2 (PAR-1; Hollenberg et al. 1997), SLIGRL-NH2 (PAR-2; al-Ani et al. 1995) and 2f-LIGKV-OH (PAR-2; Kawabata et al. 2004) and AYPGKF-NH2 (PAR-4; Hollenberg & Saifeddine, 2001), have been developed to probe the distinct functions of each receptor, although evidence suggests diligence is required when using these and other peptide agonists (Stenton et al. 2002; Hollenberg et al. 2004; Moffatt, 2004; Fig. 1). This approach, in addition to studies utilizing PAR-deficient mice, have indicated that, whilst thrombin-sensitive PARs seem to be involved in wound healing (MacFarlane et al. 2001; Strukova, 2001), thrombogenesis (MacFarlane et al. 2001; Strukova, 2004) and inflammation (Moller et al. 2000; Asokananthan et al. 2002; Suo et al. 2002; Vergnolle, 2004; Nicole et al. 2005). PAR-2, is thought primarily to play a key role in conditions associated with inflammation. Recent studies show roles in the mediation of inflammatory pain (Hoogerwerf et al. 2001; Vergnolle et al. 2001; Fiorucci & Distrutti, 2002; Dai et al. 2004), arthritis (Ferrell et al. 2003; Kelso et al. 2006) and a number of skin disorders (Steinhoff et al. 2003; Namazi, 2005), whilst other work has provided evidence for a protective, anti-inflammatory role in airways (Cocks et al. 1999; Kawabata & Kawao, 2005; Morello et al. 2005; Henry, 2006) and intestine (Kawabata et al. 2001; Fiorucci et al. 2001). These studies indicate that PAR-2 exhibits a duality of function depending upon the tissue and the disease context and, as such, considerable attention is being directed to the development of selective PAR-2 agonists and antagonists as therapeutic agents for peripheral inflammatory diseases (Scarborough, 2003; Kanke et al. 2005; Kelso et al. 2006).
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Our knowledge of PAR function in the brain is largely based on PAR-1 (for reviews see Gingrich & Traynelis, 2000; Noorbakhsh et al. 2003; Rohatgi et al. 2004); however, despite the extensive literature regarding the role of PAR-2 in the periphery, the extent of our knowledge regarding PAR-2 function in the brain is small in comparison. In situ hybridization and immunohistochemical localization studies reveal neuronal expression of PAR-2 in the rodent and human brain (D'Andrea et al. 1998; Striggow et al. 2001; Riek-Burchardt et al. 2002; Noorbakhsh et al. 2003, 2005, 2006; Jin et al. 2005; Bushell et al. 2006). Investigations into the consequence of PAR-2 activation on central neurones reveal that acute exposure of cultured hippocampal neurones to PAR-2-selective agonists elevates intracellular calcium (Ca2+) through the Gq/phospholipase C (PLC) (phospholipase C) pathway (Bushell et al. 2006). Furthermore, PAR-2 activation has been shown to be neurotoxic to cultured hippocampal neurones in a concentration-dependant manner (Smith-Swintosky et al. 1997). Interestingly, in both of these studies a heterogeneous expression of PAR-2 was observed in neurones, with a selective increased expression of PAR-2 on GABAergic neurones. Further investigation revealed that GABAergic neurones with higher levels of PAR-2 expression exhibited increased Ca2+ signalling upon exposure to agonists (Bushell et al. 2006). Although a similar heterogeneity in expression levels was not evident when investigated in slice preparations, the link between expression and function may be valuable in helping elucidate the consequence of PAR-2 up-regulation.
In addition to studies regarding neuronal PAR-2, it is now well established that the receptor is located in CNS glial cells. PAR-2 expression has been shown in astrocytes both in rodent primary cultures (Ubl et al. 1998; Wang et al. 2003; Bushell et al. 2006; Park et al. 2006) and acute brain slices (Pompilli et al. 2004; Bushell et al. 2006) as well in human white matter (Noorbakhsh et al. 2006). Similar to the findings with neuronal PAR-2, receptor activation in cultured astrocytes elicits rises in intracellular calcium levels, which has led to suggestions that astrocytic PAR-2 may play a neuroprotective and/or neurodegenerative role in the brain. In addition to astrocytic expression, PAR-2 has also recently been shown to be expressed in microglia (Goldshmidt & Traynelis, 2006; Noorbakhsh et al. 2006), cells which not only underlie the immune response within the brain but are also proposed to be involved in functions such as synaptogenesis and developmental apoptosis (Bessis et al. 2007).
PAR-2 up-regulation in disease conditions affecting the CNS
Clear evidence now exists for an up-regulation of PAR-2 expression in certain peripheral inflammatory disease states. However, is a similar up-regulation observed in experimental CNS disease models and in human tissue from patients suffering from CNS neurological disorders? The first evidence indicating PAR up-regulation was observed following exposure to severe experimental ischaemia (oxygen–glucose deprivation), which resulted in an increased expression of PAR-2, as well as other PARs, in organotypic hippocampal slice cultures (Striggow et al. 2001). A significant increase in PAR-2 was observed at 6 h which lasted until 24 h post-exposure to experimental ischaemia. However, the levels of PAR-2 exposure were not significantly altered when examined 72 h post-exposure. Despite the functional consequence of this up-regulation not being investigated, this study revealed that under experimental disease conditions, PAR-2 expression was indeed up-regulated, but over a specific time course. Similar to results observed in intestinal radiation damage (Wang et al. 2003), up-regulation of PAR-2 expression was also evident following experimental CNS radiation damage, with increased expression being observed for up to 40 days post-treatment (Olejar et al. 2002). This is significant because radiation injury is thought to occur via the activation of chronic inflammatory pathways (Monje et al. 2003). As inflammation is known to impair adult hippocampal neurogenesis (Ekdahl et al. 2003; Monje et al. 2003), which in itself may contribute to the cognitive dysfunction observed following cranial radiation therapy (Parent et al. 1999; Abayomi, 2002; Monje et al. 2002), the increase in PAR-2 expression exhibited under these conditions may contribute to the inhibition of neurogenesis. Taken together, these findings suggest a link between inflammation and PAR-2 function which appears to be common in both CNS and peripheral inflammation-induced disorders. However, the functional consequence of this up-regulation in the CNS remained unclear. The first indicator as to the role of PAR-2 was seen in in vivo models of acute focal ischaemic brain injury. In control experiments, PAR-2 was found to be significantly up-regulated up to 24 h following transient occlusion of the middle cerebral artery (tMCAO) (Jin et al. 2005), a finding similar to that previously observed following oxygen–glucose deprivation in organotypic slice cultures (Striggow et al. 2001). Furthermore, in PAR-2-deficient mice, the infarct volume following tMCAO was significantly increased when compared with wild-type controls (Jin et al. 2005) indicating a neuroprotective role for PAR-2 in this model of ischaemic brain injury.
The notion that PAR-2 activation and up-regulation is neuroprotective in nature is also supported in a study that identified an increase in neuronal PAR-2 expression in a human CNS inflammatory disorder, HIV-associated dementia (HAD; Noorbakhsh et al. 2005; Fig. 2). Real time RT-PCR experiments revealed a significant up-regulation of PAR-2 mRNA in brain tissue when compared with non-dementia-associated HIV/AIDS patients (ND). Significantly, this was also associated with comparable elevations of the inflammatory cytokines TNF- and IL-1 (Fig. 2). Immunohistochemical analysis revealed weak PAR-2 expression in neurones of ND tissue, similar to that reported previously in normal brain tissue (D'Andrea et al. 1998), but this was significantly increased in neurones from HAD patients (Fig. 2). To identify the role of PAR-2 in HAD, the consequence of PAR-2 activation was examined in a mouse model of HIV neuropathogenesis. Striatal implantation of PAR-2 APs significantly inhibited the neurotoxicity induced by the HIV-1 trans-activating protein, Tat, in control mice, whilst in PAR-2-deficient mice, an increased severity of neuroinflammation and neuronal damage occurred. This implies that PAR-2 plays a neuroprotective role in controlling HIV-induced neuropathogenesis, a finding in agreement with the experimental ischaemia study mentioned earlier.
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In both HIV dementia and MS, a relationship emerges between PAR-2 expression and elevated inflammatory cytokines levels. However, it appears that depending on whether the PAR-2 up-regulation is neuronal or glial dictates if PAR-2 activation is either neuroprotective or neurodegenerative. These findings are further confirmed in experiments performed in human neuronal cell lines and cultured microglia. Exposure of the neuronal cell lines to TNF- and IL-1 significantly increased PAR-2 expression. Furthermore, in Tat-induced neurotoxicity models performed in primary neuronal culture, TNF- was neuroprotective in wild-type cultures, whereas it proved to be neurotoxic in PAR-2-deficient cultures (Noorbakhsh et al. 2005), indicating that an increase in PAR-2 expression is responsible for the neuroprotective effect of these cytokines. Although the effects of cytokines on PAR-2 expression was not studied in cultured glia, PAR-2 activation in microglia, but not astrocytes, is associated with an increase in the expression levels of TNF-, IL-6, IL-12 and iNOS. Further, the supernatant taken from PAR-2-activated microglia is toxic to oligodendrocytes (Noorbakhsh et al. 2006), cells which are associated with demyelinating lesions in MS (Barnett & Prineas, 2004). These findings and, as mentioned earlier, the fact that PAR-2-deficient mice exhibit an decreased EAE phenotype suggest a link between PAR-2 and inflammatory cytokines in the neurodegeneration observed in MS and EAE animal models These findings are particular interesting as evidence exists for TNF- being both neuroprotective or neurotoxic depending on the system utilized and the conditions investigated (Garcia et al. 1992; Barger et al. 1995; Herman et al. 2001; Zhao et al. 2001; Sitcheran et al. 2005; Zou & Crews, 2005; Sriram et al. 2006). The link between TNF- and PAR-2 is further supported by studies which observed similar increases in infarct volume following tMCAO in mice deficient in TNF-R1 or both TNF-R1 and TNF-R2 (Bruce et al. 1996; Gary et al. 1998). In addition, mice with a genetic mutation in TNF- were more susceptible to sodium nitroprusside-induced neurodegeneration (Turrin & Rivest, 2006). These findings strongly support a close interaction between TNF- and PAR-2 and beg the question, could the potential link between either a neuroprotective or a neurotoxic effect of TNF- be the capacity for PAR-2 up-regulation in the particular cell type investigated or neurological model used?
How does PAR-2 induce neuroprotection or neurodegeneration?
The available evidence indicates that activation of PAR-2 subsequent to its up-regulation is neuroprotective or neurodegenerative depending on the cell type in which it occurs (Fig. 3), yet there are still questions about the role of PAR-2 in the CNS which remain unanswered such as what are the endogenous PAR-2 activators and what are the signalling mechanisms that underlie its neuroprotective and/or neurodegenerative effects?
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PAR-2 signalling pathways.
PARs, including PAR-2, are known to mediate their cellular effects through the activation of heteromeric G-proteins. Studies have revealed that the predominant subunit involved in mediating PAR effects is the pertussis-toxin-insensitive Gq/G11 and G12/G13 subunits (Babich et al. 1990; Offermanns et al. 1994, 1997; Vaidyula & Rao, 2003). The response to activation of these G-proteins is the elevation of intracellular Ca2+ via the phospholipase C/IP3 pathway as has been shown for PAR-2 in cultured hippocampal neurones (Smith-Swintosky et al. 1997; Bushell et al. 2006). Downstream of increases in intracellular Ca2+, PAR-2 activation stimulates numerous signalling pathways depending on the preparation utilized, for example protein kinase C (PKC), mitogen-activated protein kinases (MAPK) and stress-activated protein kinases (Belham et al. 1996; DeFea et al. 2000; Kanke et al. 2001). PAR-2 activation has also been shown to increase the activity of transient receptor potential vanilloid 1 (TRPV1) channels, a mechanism proposed to be involved in inflammatory pain (Amadesi et al. 2004, 2006; Dai et al. 2004). With TRPV1 being located in the brain (Steenland et al. 2006), its modulation by PAR-2 may be an intriguing avenue to explore with regard to TRPV1 function in relation to central pain processing and other non-pain-related functions. Recently, neuronal PAR-2 has been linked to the stimulation of the extracellular signal-regulated kinase (ERK) subfamily of MAPK following tMCAO (Jin et al. 2005). The increase in ERK activity was neurone specific and was significantly inhibited in PAR-2 KO mice. As an increase in ERK activity is proposed to be beneficial to neuronal survival (Hetman & Xia, 2000; Li et al. 2003; Mocchetti & Bachis, 2004), this suggests the neuroprotective role of PAR-2 observed in this study is directly linked to ERK activation. This raises an interesting issue as to PAR-2 signalling in the CNS. The activation of ERK by PAR-2 is thought to rely on the -arrestin-dependant internalization of the receptor and the formation of a signalling complex (DeFea et al. 2000). Although the internalization and the formation of a signalling complex are not required for ERK activation per se (DeFea et al. 2000; Seatter et al. 2004; Stalheim et al. 2005), it may be required for appropriate subcellular localization and functioning of ERK. In contrast to the rapid PAR-2 internalization observed in heterologous expression systems and peripheral tissue (Bohm et al. 1996; Dery et al. 1999; DeFea et al. 2000; Seatter et al. 2004; Stalheim et al. 2005), prolonged exposure of cultured hippocampal neurones to trypsin does not result in receptor internalization (Bushell et al. 2006). Similar findings have also been reported for other GPCRs when investigated in neurones (Coutts et al. 2001; Bushell et al. 2002). This leads to further questions such as is PAR-2 internalization required for the observed ERK activation and it's neuroprotective effects or is the lack of internalization in cultured neurones an artefact of the preparation/neurone type used.
Similarities exist in the signalling pathways activated following neuronal and astrocytic PAR-2 activation. Astrocytic receptor activation induces the reversal of astrocytic stellation (Park et al. 2006), a change in astrocytic morphology which has been shown to occur under a variety of pathological conditions (Norton et al. 1992; Sofroniew, 2005). The reversal of stellation occurs in a Ca2+- and PKC-dependant manner, signalling pathways similar to those described earlier for neuronal PAR-2. However, a novel PAR-2 signalling pathway has recently been identified following astrocytic PAR-2 activation with receptor activation leading to the release of GRO/CINC1, a rat counterpart of human interleukin-8, from cultured astrocytes (Wang et al. 2007). This release is independent of PKC, phosphoinositide3-kinase and MAPK kinase (MEK) whereas c-Jun N-terminal kinase 1 (JNK1) plays a pivotal role. Under these conditions, the receptor-induced release of this chemokine is shown to be neuroprotective as astrocytes are protected from ceramide-induced cell death.
Conclusion
Recent findings have increased our understanding of PAR-2 function in the CNS; however, questions still remain. Evidence pertaining to the endogenous activators of the receptor and the potential signalling mechanisms involved in the observed neuroprotection and/or degeneration is discussed in this review. However, whether PAR-2 displays a duality of function depending on (1) the levels of receptor up-regulation, with low level up-regulation being neuroprotective whilst high level up-regulation exacerbates disease conditions, and/or (2) the cell type in which PAR-2 up-regulation occurs, remains to be investigated. These are important questions, the answer to which will further our appreciation of the role of PAR-2 in the CNS. The link between PAR-2 and the numerous inflammatory cytokines also requires further investigation as the interactions between them are likely to be complex in nature and may underlie the contrasting neuroprotective and neurotoxic effects observed with TNF-. However, despite the emerging evidence linking PAR-2 with CNS disorders, it is important to realize that we are at an early stage in fully understanding its role in the CNS, and further investigation is required before we can unequivocally state that PAR-2 plays a role in CNS disorders. Nevertheless, the finding that PAR-2 potentially plays a neuroprotective and/or neurodegenerative role in the CNS presents the receptor as a theoretical novel target for the treatment of CNS disorders particularly those in which inflammation is thought to play an intrinsic role.
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