Elsevier

Neuropharmacology

Volume 96, Part A, September 2015, Pages 70-82
Neuropharmacology

Invited review
Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability

https://doi.org/10.1016/j.neuropharm.2014.10.027Get rights and content

Highlights

  • Cytokines display a direct neuromodulatory role in CNS and PNS.

  • Cytokines modulate VGC and ROC and presynaptic neurotransmitter release.

  • Cytokines affect neuronal excitability also indirectly by activating glial cells.

  • Cytokines have a physiological role in synaptic transmission and plasticity.

  • Excessive cell exposure to cytokines may mediate neuropathologic effects.

Abstract

Increasing evidence underlines that prototypical inflammatory cytokines (IL-1β, TNF-α and IL-6) either synthesized in the central (CNS) or peripheral nervous system (PNS) by resident cells, or imported by immune blood cells, are involved in several pathophysiological functions, including an unexpected impact on synaptic transmission and neuronal excitability.

This review describes these unconventional neuromodulatory properties of cytokines, that are distinct from their classical action as effector molecules of the immune system. In addition to the role of cytokines in brain physiology, we report evidence that dysregulation of their biosynthesis and cellular release, or alterations in receptor-mediated intracellular pathways in target cells, leads to neuronal cell dysfunction and modifications in neuronal network excitability. As a consequence, targeting of these cytokines, and related signalling molecules, is considered a novel option for the development of therapies in various CNS or PNS disorders associated with an inflammatory component.

This article is part of a Special Issue entitled ‘Neuroimmunology and Synaptic Function’.

Introduction

Cytokines are a large family of soluble peptides and proteins released by immune cell, representing key regulators of the prototypical innate and adaptive immune response to infection. Increasing experimental evidence has shown that cytokines, and related effector molecules, in addition to their canonical involvement in the tissue response to infection, are endowed with specific neuromodulatory functions.

In the central (CNS) and peripheral (PNS) nervous system, both glia and neurons, together with endothelial cells of the microvasculature, release cytokines and express their cognate receptors. Cytokines are, therefore, soluble mediators of a complex paracrine and autocrine cross-talk between different cell populations in the nervous system. Cytokines can modulate neuronal activity and viability either indirectly by promoting the release of neuroactive molecules from glia or the endothelium (e.g, nitric oxide, glutamate, prostaglandins, neurotrophins) (Allan and Rothwell, 2001, Montgomery and Bowers, 2012), or directly by activating their neuronal receptors in the brain and spinal cord (Marin and Kipnis, 2013, Vezzani et al., 2011a, Viviani et al., 2007, Zhang et al., 2014). In support of a direct cytokine effect on neurons, there is evidence that highly purified neurons in vitro (with less than 2% glia contamination) do express functional cytokine receptors (Viviani et al., 2003, Gardoni et al., 2011, Stellwagen et al., 2005). Moreover, IL-1 receptor type 1 (IL-1R1), that mediates the biological actions of IL-1β, is enriched in a purified post-synaptic density fraction in rat hippocampus and cortex (Gardoni et al., 2011, Viviani et al., 2014), and is associated to a signal transduction accessory protein (IL-1R AcPb) specifically expressed by neurons (Huang et al., 2011). Additional evidence for neuronal, as well as glial and vessel-associated cytokine receptors, is provided by in vivo studies showing receptor expression in phenotypically identified brain and spinal cord cells (Hopkins and Rothwell, 1995, Vezzani et al., 2011b). This relatively new knowledge underscores that the immune and nervous systems do not operate autonomously but they mutually affect each others function (Kelley and McCusker, 2014).

Classical inflammatory cytokines, such as IL-1β, TNF-α and IL-6, by activating their cognate receptors in target cells, induce intracellular pathways which differ depending on the cell type, and often result in divergent pathophysiologic outcomes. In the nervous system, cytokines have physiological functions that include neurite outgrowth, neurogenesis, neuronal survival, synaptic pruning during brain development, and they regulate the strength of synaptic transmission and synaptic plasticity (Marin and Kipnis, 2013). However, the over-production and exaggerated release of cytokines, or their protracted presence in tissue, is associated with neuronal dysfunctions, as described in neuropathic pain (Zhang et al., 2014), psychiatric disorders, neurodegenerative diseases and epilepsy (Allan et al., 2005, Glass et al., 2010, Nguyen et al., 2002, Vezzani et al., 2011b, Devinsky et al., 2013, Griffin, 2006) (Fig. 1).

The focus of this review is on the neuromodulatory effects of IL-1β, TNF-α and IL-6, specifically on their ability to modulate ion channels activity, and their distribution in neuronal membranes. We discuss how cytokines contribute to synaptic function and plasticity (Marin and Kipnis, 2013, Santello and Volterra, 2012, Vitkovic et al., 2000, Yirmiya and Goshen, 2011), and in which circumstances they contribute to neuropathology (Allan et al., 2005, Centonze et al., 2010, Galic et al., 2012, Glass et al., 2010, Nguyen et al., 2002, Vezzani et al., 2011a), therefore supporting their role in nervous system diseases associated with an inflammatory component.

Section snippets

Cellular sources of cytokines

Cytokine levels in blood and nervous tissue are relatively low in physiological conditions (≤1 pg in 1 ml or mg) but a several-fold increase rapidly occurs after various CNS or PNS injuries, seizures or infection. The prevailing view is that a controlled and timely production of cytokines is required for normal tissue function while dysregulation in their biosynthesis, release or cell signalling results in deficits in synaptic plasticity and contributes to neuropathology (Gerber et al., 2004,

Modulation of voltage-gated ion channels

Voltage-gated channels (VGCs) are regulated by a change in membrane voltage, which allows channels opening upon membrane depolarization and the consequent flow of ions down their electrochemical gradient. Ion channels differ from each others by (i) their ability to discriminate between ion species (i.e. selectivity for Na+, Ca2+, K+), (ii) the modality of their activation (i.e. low or high activating threshold) or inactivation (i.e. slow or fast-inactivating) and (iii) their ionic conductance (

Modulation of receptor-coupled ion channels in CNS

Although the effect of cytokines on VGCs in CNS neurons are largely inhibitory, excitatory effects are often reported on receptor-operated ion channels (ROCs), particularly in hippocampal slices or cultured forebrain neurons (Table 1) (Viviani et al., 2007, Wang et al., 2000, Zeise et al., 1997).

Cytokines and the microvasculature

The presence of IL-1R1 and TNF-R1 in endothelial cells supports the functional evidence that cytokines impair the permeability properties of the BBB, by promoting the disassembling of the tight junctions, the production of nitric oxide and the activation of matrix methalloproteinases (Allan et al., 2005, de Vries et al., 1996, Librizzi et al., 2012, Morin-Brureau et al., 2011, Wright and Merchant, 1994). These BBB-related effects can impact neuronal excitability via brain extravasation of serum

Long-term effects of cytokines on brain pathophysiology

A peculiar feature of cytokines is to induce long-term effects on brain physiology even after a transient raise of their levels, as provoked either by a systemic or an intracerebral inflammatory challenge. Supporting evidence largely relates to inflammatory stimuli imposed to rodents during their embryonic life, or early post-natal development. The ensuing long-term changes in brain physiology are likely due to cytokine influence on neuronal stem cells proliferation and migration, axonal

Conclusions

This review reports examples of the complex effects of cytokines in CNS and PNS neurons, by describing the array of changes they provoke on VGCs and ROCs function, as well as the post-translational and transcriptional cellular pathways underlying these neuromodulatory effects.

Although remarkable progress has been achieved in our knowledge and understanding of the neuromodulatory role of cytokines, there are, however, a number of unanswered questions. In particular, it appears unresolved which

Acknowledgements

Supported by Fondazione Monzino, Epitarget (FP7/2007-2013, grant agreement n°602102) and Ministero della Salute (RF-2009-1506142) (AV).

References (187)

  • A.J. Cunningham et al.

    Interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro

    Neurosci. Lett.

    (1996)
  • J.C. Czeschik et al.

    TNF-alpha differentially modulates ion channels of nociceptive neurons

    Neurosci. Lett.

    (2008)
  • V. De Chiara et al.

    Interleukin-1beta alters the sensitivity of cannabinoid CB1 receptors controlling glutamate transmission in the striatum

    Neuroscience

    (2013)
  • H.E. de Vries et al.

    The influence of cytokines on the integrity of the blood–brain barrier in vitro

    J. Neuroimmunol.

    (1996)
  • O. Devinsky et al.

    Glia and epilepsy: excitability and inflammation

    Trends Neurosci.

    (2013)
  • R. Diem et al.

    Interleukin-1 beta protects neurons via the interleukin-1 (IL-1) receptor-mediated Akt pathway and by IL-1 receptor-independent decrease of transmembrane currents in vivo

    Mol. Cell. Neurosci.

    (2003)
  • C.A. Dinarello

    Biologic basis for interleukin-1 in disease

    Blood

    (1996)
  • T. Fellin et al.

    Do astrocytes contribute to excitation underlying seizures?

    Trends Mol. Med.

    (2005)
  • M.A. Galic et al.

    Cytokines and brain excitability

    Front. Neuroendocrinol.

    (2012)
  • F. Garcia-Oscos et al.

    The stress-induced cytokine interleukin-6 decreases the inhibition/excitation ratio in the rat temporal cortex via trans-signalling

    Biol. Psychiatry

    (2012)
  • J. Gerber et al.

    Increased mortality and spatial memory deficits in TNF-alpha-deficient mice in ceftriaxone-treated experimental pneumococcal meningitis

    Neurobiol. Dis.

    (2004)
  • S. Girard et al.

    Postnatal administration of IL-1Ra exerts neuroprotective effects following perinatal inflammation and/or hypoxic-ischemic injuries

    Brain Behav. Immun.

    (2012)
  • C.K. Glass et al.

    Mechanisms underlying inflammation in neurodegeneration

    Cell

    (2010)
  • I. Goshen et al.

    A dual role for interleukin-1 in hippocampal-dependent memory processes

    Psychoneuroendocrinology

    (2007)
  • M. Grell et al.

    The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor

    Cell

    (1995)
  • W.S. Griffin

    Inflammation and neurodegenerative diseases

    Am. J. Clin. Nutr.

    (2006)
  • M.M. Halassa et al.

    The tripartite synapse: roles for gliotransmission in health and disease

    Trends Mol. Med.

    (2007)
  • X.H. He et al.

    TNF-alpha contributes to up-regulation of Nav1.3 and Nav1.8 in DRG neurons following motor fiber injury

    Pain

    (2010)
  • S.J. Hopkins et al.

    Cytokines and the nervous system. I: expression and recognition

    Trends Neurosci.

    (1995)
  • K.F. Huang et al.

    Interleukin-1 receptor antagonist inhibits the release of glutamate, hydroxyl radicals, and prostaglandin E(2) in the hypothalamus during pyrogen-induced fever in rabbits

    Eur. J. Pharmacol.

    (2010)
  • H. Katsuki et al.

    Interleukin-1 beta inhibits long-term potentiation in the CA3 region of mouse hippocampal slices

    Eur. J. Pharmacol.

    (1990)
  • R.A. Kohman et al.

    Neonatal endotoxin exposure impairs avoidance learning and attenuates endotoxin-induced sickness behavior and central IL-1beta gene transcription in adulthood

    Behav. Brain Res.

    (2008)
  • L. Ladepeche et al.

    Surface trafficking of NMDA receptors: gathering from a partner to another

    Semin. Cell Dev. Biol.

    (2014)
  • A.Y. Lai et al.

    Interleukin-1 beta modulates AMPA receptor expression and phosphorylation in hippocampal neurons

    J. Neuroimmunol.

    (2006)
  • F. Lante et al.

    Neurodevelopmental damage after prenatal infection: role of oxidative stress in the fetal brain

    Free Radic. Biol. Med.

    (2007)
  • C.E. Loscher et al.

    Interleukin-1 receptor antagonist exerts agonist activity in the hippocampus independent of the interleukin-1 type I receptor

    J. Neuroimmunol.

    (2003)
  • A. MacManus et al.

    Enhancement of (45)Ca(2+) influx and voltage-dependent Ca(2+) channel activity by beta-amyloid-(1-40) in rat cortical synaptosomes and cultured cortical neurons. Modulation by the proinflammatory cytokine interleukin-1beta

    J. Biol. Chem.

    (2000)
  • J. Marcon et al.

    Age-dependent vascular changes induced by status epilepticus in rat forebrain: implications for epileptogenesis

    Neurobiol. Dis.

    (2009)
  • J. McAfoose et al.

    Evidence for a cytokine model of cognitive function

    Neurosci. Biobehav. Rev.

    (2009)
  • U. Meyer et al.

    Preliminary evidence for a modulation of fetal dopaminergic development by maternal immune activation during pregnancy

    Neuroscience

    (2008)
  • S.M. Allan et al.

    Cytokines and acute neurodegeneration

    Nat. Rev. Neurosci.

    (2001)
  • S.M. Allan et al.

    Interleukin-1 and neuronal injury

    Nat. Rev. Immunol.

    (2005)
  • R. Andre et al.

    Gene regulation by IL-1beta independent of IL-1R1 in the mouse brain

    Glia

    (2006)
  • A. Avital et al.

    Impaired interleukin-1 signalling is associated with deficits in hippocampal memory processes and neural plasticity

    Hippocampus

    (2003)
  • S. Balosso et al.

    A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1beta

    Brain

    (2008)
  • S. Balosso et al.

    Tumor necrosis factor-alpha inhibits seizures in mice via p75 receptors

    Ann. Neurol.

    (2005)
  • D. Balschun et al.

    Interleukin-6: a cytokine to forget

    FASEB J.

    (2004)
  • E.C. Beattie et al.

    Control of synaptic strength by glial TNFalpha

    Science

    (2002)
  • S. Bevan et al.

    Trpv1

    Handb. Exp. Pharmacol.

    (2014)
  • P. Bezzi et al.

    CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity

    Nat. Neurosci.

    (2001)
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