Invited Review
IL-1 receptor/Toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures

https://doi.org/10.1016/j.bbi.2011.03.018Get rights and content

Abstract

Increasing evidence supports the involvement of immune and inflammatory processes in the etiopathogenesis of seizures. In particular, activation of innate immune mechanisms and the subsequent inflammatory responses, that are induced in the brain by infection, febrile seizures, neurotrauma, stroke are well documented conditions associated with acute symptomatic seizures and with a high risk of developing epilepsy. A decade ago, pharmacological experiments showed that elevated brain levels of the anti-inflammatory molecule IL-1 receptor antagonist reduced seizures in epilepsy models. This observation, together with the evidence of in situ induction of inflammatory mediators and their receptors in experimental and human epileptogenic brain tissue, established the proof-of-concept evidence that the activation of innate immunity and inflammation in the brain are intrinsic features of the pathologic hyperexcitable tissue.

Recent breakthroughs in understanding the molecular organization of the innate immune system first in macrophages, then in the different cell types of the CNS, together with pharmacological and genetic studies in epilepsy models, showed that the activation of IL-1 receptor/Toll-like receptor (IL-1R/TLR) signaling significantly contributes to seizures. IL-1R/TLR mediated pro-excitatory actions are elicited in the brain either by mimicking bacterial or viral infections and inflammatory responses, or via the action of endogenous ligands. These ligands include proinflammatory cytokines, such as IL-1beta, or danger signals, such as HMGB1, released from activated or injured cells. The IL-1R/TLR signaling mediates rapid post-translational changes in voltage- and ligand-gated ion channels that increase excitability, and transcriptional changes in genes involved in neurotransmission and synaptic plasticity that contribute to lower seizure thresholds chronically.

The anticonvulsant effects of inhibitors of the IL-1R/TLR signaling in various seizures models suggest that this system could be targeted to inhibit seizures in presently pharmaco-resistant epilepsies.

Highlight

► IL-1R/TLR signaling activation by IL-1β, DAMPs or PAMPs decreases seizure threshold in epilepsy and can be targeted to attain anticonvulsant effects.

Introduction

Seizures, the hallmarks of epilepsy, originate from synchronized aberrant firing of neuronal populations due to underlying hyperexcitability phenomena. In the last decade, studies on the mechanisms underlying seizures showed that glial cells importantly contribute to neuronal network dysfunctions. Disease-related alteration in astrocyte and microglia functions include changes in the expression of ion and water channels, glutamate receptors and transporter, intracellular Ca2+ signaling and activation of astrocytic gliotransmission (Hanisch and Kettenmann, 2007, Seifert et al., 2006). Recently, the crucial role played in the mechanisms of seizures by proinflammatory cytokines synthesized and released mostly, although not exclusively, by activated glial cells has gained increasing recognition (Vezzani et al., 2008, Vezzani et al., 2011).

It is well established that proinflammatory cytokines in addition to their canonical involvement in immune response activation following infection, can subserve neuromodulatory functions implicated in brain physiology and may contribute to acute and chronic neurodegeneration (Allan et al., 2005, Glass et al., 2010, Nguyen et al., 2002). The possibility that cytokines also contribute to aberrant neuronal excitability underlying seizures is supported by clinical and experimental findings.

Inflammatory mediators and their receptors are up-regulated in microglia and astrocytes in epileptogenic brain tissue from clinical cases of drug-resistant epilepsies of different etiology, similarly to what is described in brain areas recruited in experimentally induced epileptic activity, like the cerebral cortex and limbic structures (Choi et al., 2009, Vezzani et al., 2011). In these brain areas, neurons and endothelial cells of the blood–brain barrier (BBB) also express proinflammatory cytokines. The frequent concomitant over-expression of releasable inflammatory mediators and of their functional receptors in the same cell types, is evidence for the activation of both autocrine and paracrine inflammatory signaling in the epileptic tissue. The extent of brain inflammation positively correlates with the frequency of seizures and with the severity of neuropathology both in patients and in animal models (Iyer et al., 2010, Ravizza et al., 2006a, Ravizza et al., 2008), suggesting a causal relationship between inflammation and seizures.

The active role in seizures of brain-derived inflammatory molecules, and the activation of the related cell signaling, has been demonstrated by various experimental observations. In particular, pro-epileptogenic injuries activate specific inflammatory pathways that contribute to the precipitation and recurrence of seizures (Bartfai et al., 2007, Vezzani et al., 2011). Moreover, the experimental induction of a proinflammatory state in the CNS, mimicking bacterial or viral infections, mediates long-term changes in brain excitability, and increases the likelihood of seizure precipitation (Riazi et al., 2010). This set of experimental evidence is concordant with the clinical observations that inflammatory processes are induced in brain following infection, neurotrauma, stroke, febrile seizures, status epilepticus, which are all events associated with the occurrence of symptomatic seizures and with an increased risk of developing epilepsy (Bartfai et al., 2007, Herman, 2002). Notably, infection and fever, which are concomitant with increased levels of pro-inflammatory cytokines not only in the periphery but also in the brain, can be precipitating events of seizures; moreover, a causal link between CNS infection and epilepsy has been proposed (Singh et al., 2008). It is therefore possible that microbial pathogens and non-infectious pro-epileptogenic brain insults induce common molecules and common signaling pathways in the brain, that may contribute via converging cellular and molecular mechanisms to the development of the epileptic process. BBB breakdown which often accompanies major systemic or CNS insults (Carvey et al., 2009, Oby and Janigro, 2006, Shlosberg et al., 2010) or active transport systems across the BBB (Banks et al., 1989) may also contribute to the entry of activators of the IL-1R/TLR signaling from the blood stream (Bianchi, 2007, Zhang et al., 2010b).

In the context of convergence of brain injury or infection and the epileptic process, an obvious candidate mechanism is represented by the IL-1 receptor/Toll-like receptor (IL-1R/TLR) signaling. This signaling is pivotal for activation of innate immunity and inflammation, and it may occur either following TLR mediated recognition of pathogens, or through binding of proinflammatory molecules such as IL-1β, or danger signals, such as HMGB1, released from activated or injured cells (Bianchi, 2007, Nguyen et al., 2002).

In this article, we will review the recent evidence on the role of the prototypical proinflammatory IL-1R/TLR signaling in seizures, following its activation by endogenous molecules, or by ligands mimicking bacterial or viral infections. We will discuss the cellular sources and the molecular targets of the activators of this signaling pathway, the molecular mechanisms by which IL-1R/TLR signaling may alter neuronal excitability, and the opportunities for therapeutic intervention emerging from the identification of the pro-convulsant role of this inflammatory pathway.

Section snippets

The IL-1R/TLR signaling

IL-1R/TLR superfamily of single transmembrane domain receptors comprises 24 members (including five adaptor proteins) which share a cytosolic domain named the Toll/IL-1 receptor (TIR) domain (O’Neill and Bowie, 2007). Agonist binding to the extracellular domain of this family of receptors, and the subsequent recruitment of MyD88 and other cytosolic adaptor proteins, activates signaling via IRAK1/4 and TRAF6 to induce the expression of many genes involved in immunity and inflammation, under the

Brain expression of IL-1R1 and TLRs

The expression and function of these receptors was originally described in lymphoid cells and tissues; more recently, they have been identified in parenchymal brain cells where they subserve physiopathological functions. In particular, IL-1R1, TLR2, TLR3 and TLR4 mRNA are expressed in rodent microglia cells, astrocytes and neurons, and in ependymal cells lining the cerebral ventricles. Expression of these receptors has been reported also in endothelial cells of the BBB (Alheim and Bartfai, 1998

IL-1R/TLR signaling and neuronal excitability

The constitutive presence of IL-1R1 and TLRs, and their endogenous ligands, in CNS support their role in brain physiology. Recent findings provide a link between the activation of some of these receptors (i.e. IL-1R1, TLR4 and TLR3) and rapid changes in neuronal excitability, highlighting novel mechanisms mediated by IL-1R/TLR signaling, and showing that its activation can occur also independently on acute or chronic neurodegeneration.

IL-1R/TLR signaling in seizures

Pharmacologic and genetic studies showed that cytokines (e.g. IL-1β, TNF-α), danger signals (e.g. HMGB1) and down-stream activated systems such as complement factors (e.g. MAC complex) and prostaglandins (e.g. PGE2), significantly contribute to seizure activity and cell loss (Kulkarni and Dhir, 2009, Riazi et al., 2010, Vezzani et al., 2011). These molecules are induced by proconvulsant events or by pathogens mimicry, and they promote seizures either by rapid direct post-translational actions

Conclusions and perspectives

In the past decade progress has been made in understanding of the role of innate immunity and the associated inflammatory processes in brain pathology. In particular, in understanding the neurobiology of epilepsy it is important that we gained recognition of the role of astrocytes and microglia in the etiopathogenesis of seizures, and that we acknowledge astrocytes and neurons as active players in the mechanisms of innate immunity and inflammation, which was considered for many years a

Acknowledgments

The authors are grateful to their sources of support: EPICURE (LSH-CT-2006-037315), Fondazione Monzino, Parents Against Childhood Epilepsy (PACE) and Cariplo Foundation (AV). Mattia Maroso received a fellowship from NeuroGlia (EU-FP7-project 202167).

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