Inflammation has an important role in the development and progression of both acute and chronic neuronal injury. Increasing evidences have shown that neurotransmitters released from nerve terminals are involved not only in the communication between neurons, but also between nerve terminals and glial cells including microglia. Most forms of neuronal injury have been associated with excitotoxicity, i.e. excessive release of excitatory amino acids such as glutamate, and subsequent activation of NMDA and AMPA/Kainate receptors (Choi, 1992; Zimmer et al., 2000; Kristensen et al., 2001; Bonde et al., 2005). Besides glutamate, ATP is a co-transmitter also released by injured or dying neurons following brain insults (Dubyak and el-Moatassim, 1993; Cunha and Ribeiro, 2000).
Microglia expresses both ionotropic and metabotropic glutamatergic receptors, that when overactivated in pathological conditions induce microglia activation and subsequent release of pro-inflammatory cytokines such as TNF-a (Noda et al., 2000; Taylor et al., 2005) . ATP can also modulate microglial activation, chemotaxis and release of cytokines, via interaction with both metabotropic (P2YR) and ionotropic (P2XR) receptors (Ferrari et al., 1996, 1997a, b, 2006; Hide et al., 2000; Sanz and Di Virgilio, 2000; Honda et al., 2001; James and Butt, 2002; Boucsein et al., 2003; Nakajima and Kohsaka, 2004; Suzuki et al., 2004; Bernardino, unpublished data). Among P2 receptors, P2X7R require higher concentrations of ATP to be activated and mediate microglial response to injury (Ferrari et al., 1997b; Di Virgilio et al., 1999; Inoue, 2002). Extracellular ATP acting via P2X7 receptors is a powerful stimulus for the maturation and release of IL-1P leading to activation of ICE/caspase-1, in the presence of an inflammatory environment, as mimicked by cell exposure to LPS (Ferrari et al., 1997a, b; Perregaux and Gabel, 1998; Sanz and Virgilio, 2000; Solle et al., 2001; Bernardino, unpublished data). Moreover, a prolonged activation of P2X7 receptors can induce the formation of a multimeric pore-like structure allowing the influx of large molecules (up to 900 Da) eventually resulting in cell death (Ferrari et al., 1999; Brough et al., 2002; Le Feuvre et al., 2002; Sylte et al., 2005; Bernardino, unpublished data).
Thus, glutamate and ATP, play important roles in modulating microglia activation and in determining the fate and extent of neuronal injury. Depending on the specific injury and inflammatory environment, activated microglia cells can be either detrimental or protective (McCluskey and Lampson, 2000). Both IL-1P and TNF-a can be neuroprotective and/or neurotoxic, contributing directly or indirectly to the initiation, maintenance, and outcome of several forms of neuronal cell death, including acute insults such as ischemia, trauma, and seizures (Barone et al., 1997; Tamatani et al., 1999; Vezzani et al., 1999, 2000; Allan and
Rothwell, 2001; Pringle et al., 2001; Shandra et al., 2002; Balosso et al., 2005; Lu et al., 2005; Patel et al., 2006) and chronic neurodegenerative disorders such as Parkinson's and Alzheimer's disease (Barger et al., 1995; Sriram et al., 2002; Wang et al., 2005a; Griffin et al., 2006).
Several mechanisms have been identified to modulate the neuroprotective and neurotoxic actions of TNF-a and IL-1ß. The neuroprotection afforded by TNF-a may depend on the ability of TNF-a to promote maintenance of calcium homeostasis by increasing expression of calbindin (Cheng et al., 1994; Mattson et al., 1995) to stimulate antioxidant pathways (Barger et al., 1995; Tamatani et al., 1999; Wilde et al., 2000) to increase transient outward potassium currents (Houzen et al., 1997) to increase membrane microglia glutamate transporter EAAT2/GLT-1 (Persson et al., 2005) or neuronal glutamate transporter EAAT3/EAAC1 (Pradillo et al., 2006) expression, promoting clearance of glutamate from the extracellular space. Besides, TNF-a may also mediate neuroprotection by a mechanism coupled to the activation of transcription factors such as NFkB (Furukawa and Mattson, 1998). Experiments carried out in knock-out mice for both TNF-a receptors (TNFR1 and TNFR2) exposed to excitotoxic/ischemic injury, showed that these mice had higher susceptibility to cell damage suggesting that the insult-induced production of TNF-a causes the up-regulation of neuronal apoptosis inhibitor protein, and consequent inhibition of apoptosis and neuroprotection (Thompson et al., 2004). Recently, Turrin and Rivest have shown that endogenous TNF-a released in response to acute nitric oxide toxicity, can be neuroprotective by triggering an immediate microglial reactivity, which helps to eliminate cell debris, restricting subsequent damage, and restoring homeostasis (Turrin and Rivest, 2006).
On the other side, there are also evidences for a neurotoxic role mediated by TNF-a (Hermann et al., 2001; Bernardino et al., 2005a; Zou and Crews, 2005). Accordingly, it was described that TNF-a increases neuronal vulnerability to excitotoxic injury by increasing the surface expression of the GluR1 subunit of the AMPA receptor (Beattie et al., 2002; Yu et al.,
2002) and by inducing upregulation of calcium permeable AMPA/kainate channels (Ogoshi et al., 2005). Furthermore, it was reported that TNF-a can inhibit astroglial glutamate transporters such as EAAT2/GLT-1, resulting in the increase of extracellular glutamate concentrations and the subsequent predisposition for glutamate excitotoxicity (Hu et al., 2000; Zou and Crews, 2005). Recently, Takeuchi and colleagues had shown that TNF-a induces neurotoxicity via glutamate release from connexin hemichannels of activated microglia. Thus, glutamate released by activated microglia induces excitotoxicity and may contribute to neuronal damage in neurodegenerative diseases (Takeuchi et al., 2006) (Fig. 3).
Both neuroprotective and neurotoxic effects may depend on local microenvironment concentrations and receptors activated. In accordance, it was shown that high concentrations of TNF-a exert protective effects on Shigella dysenteriae--induced seizures (Yuhas et al.,
2003), whereas lower concentrations were pro-convulsive (Yuhas et al., 1999). We reported that TNF-a exacerbates AMPA-induced neuronal death at relatively high doses, while lower doses of TNF-a had a neuroprotective effect (Bernardino et al., 2005a). Using organotypic cultures of mouse hippocampal slices obtained from TNFR1 -/- and TNFR2 -/- we showed that this duality reflects the balance between multiple signals derived from both receptor subtypes. Changes in the activated receptor subtype (TNFR1 or TNFR2) can affect the overall balance of excitatory to inhibitory inputs and lead to opposite effects. Thus, the mechanisms modulating the expression of these two receptors may determine neuronal/glial response to TNF-a and the consequences of inflammatory reactions in the brain (Beutler and van Huffel, 1994). Several studies showed dissociation between the neurotoxic and neuroprotective effects using knock-out rodents for each receptor or for both receptors. In accordance, it was shown that TNF-a potentiation of glutamate/AMPA excitotoxicity depends on the activation of TNFR1 receptors which contain an intracellular "death domain" and also contributes mainly to cell death on target cells (Fontaine et al., 2002; Yang et al., 2002; Bernardino et al., 2005a; Taylor et al., 2005). Supporting this evidence, Shinoda and colleagues demonstrated that kainate-induced seizures promote the formation of a molecular scaffolding complex that includes TNFR1 receptors (Shinoda et al., 2003). This complex, through death-domains and apoptosis signal-regulating kinase 1 (ASK1), can promote cell death, suggesting that the TNF-a released after the insult can activate this receptor and contribute to neuronal death. Furthermore, others showed that absence of TNFR1 led to a strong reduction of neurodegeneration in a model of retinal ischemia, while lack of TNFR2 led to an enhancement of neurodegeneration clearly indicating that TNFR1 augment neuronal death and TNFR2 promote neuroprotection (Fontaine et al., 2002). Moreover, TNFR2-induced sustained NFkB activation was essential for neuronal survival (Marchetti et al., 2004) (Fig. 3).
Besides TNF-a, also IL-1P can have both neuroprotective and neurotoxic effects in the modulation of brain excitotoxicity. Possible mechanisms by which IL-1P potentiates neuronal excitotoxicity, may involve induction of COX-2 and related prostanoids (Serou et al., 1999), iNOS (Murakami et al., 2002) and increased synthesis of superoxide and peroxynitrite (Fink et al., 1999). Inhibition of astroglial glutamate re-uptake by IL-1P (Ye and Sontheimer, 1996; Hu et al., 2000) and enhanced astrocytic glutamate release either directly or via the production of TNF-a (Bezzi et al., 1999) can result in more extracellular glutamate, thus priming neuronal vulnerability to subsequent insults. An alternative mechanism may involve functional interactions between IL-1RI and AMPA receptors leading to an increase in inward Ca2+ currents. Previous evidence has thus shown that IL-1P can increase NMDA-receptor function in hippocampal neurons by activation of tyrosine kinases, resulting in an increased susceptibility of neurons to glutamate mediated cell loss (Viviani et al., 2003). Furthermore, Lai and colleagues showed that IL-1P impairs memory functions and long-term potentiation (LTP) by selectively down-regulating the surface expression and Ser831 phosphorylation of the AMPA receptor subunit GluR1 (Lai et al., 2006). In vivo studies indicated that intra-hippocampal injection of IL-1P activates kainate-induced pro-convulsant mechanisms that contribute to the increase in the duration of electroencephalographic recorded seizures (Vezzani et al., 1999), an effect blocked by IL-1ra (Vezzani et al., 2000). On the other hand, other studies also involved the GABAergic system and GABAA receptor in the pro-convulsant effect of IL-1P (Miller et al., 1991; Luk et al., 1999).
Similarly to TNF-a, IL-1P can play also a potential neuroprotective role depending on the dosage and the experimental conditions used. In mice organotypic hippocampal slice cultures we found that IL-1P exacerbated AMPA-induced neuronal death at relatively low doses, while higher doses of IL-1P had a neuroprotective role (Bernardino et al., 2005a). Important functional crosstalk was identified between IL-1P and neurotrophic factors (e.g. NGF, CNTF) and this interaction may, in part, account for the neuroprotective role attributed to IL-1P (Strijbos and Rothwell, 1995; Herx et al., 2000; Miyachi et al., 2001). Furthermore, recently it has been shown that IL-1P can also be neuroprotective by down-regulating L-type Ca2+ channel activity in neurons, thus preventing excessive Ca2+ entry (Zhou et al., 2006). Recent studies showed that IL-1P suppresses development of focal and generalized seizures in the amygdala kindling model of epilepsy, mediated, in part, by nitric oxide and prostaglandins (Sayyah et al., 2005). Most of the reports discussed above show that the effects of IL-1P were mediated mainly through IL-1RI, since they were inhibited in the presence of IL-1ra. Accordingly, it was reported that endogenous IL-1ra, mainly released by microglial cells in response to an excitotoxic insult, regulates and inhibits the neurotoxic effects mediated by IL-1P on neurons (Pinteaux et al., 2006) (Fig. 3).
Since both TNF-a and IL-1P affect differentially the outcome of various brain injuries by interfering either in neuronal and glial cell functions, pharmacological approaches specifically targeted to manipulate the diverse effects TNF-a and IL-1P and its signaling mechanisms in diseased conditions may reveal new targets for therapeutic strategies in several CNS diseases.
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