Invited reviewNeuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability
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).
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