Functional crosstalk in culture between macrophages and trigeminal sensory neurons of a mouse genetic model of migraine

Franceschini, Alessia; Nair, Asha S.; Bele, Tanja; Maagdenberg, Arn M. J. M. van den; Nistri, Andrea; Fabbretti, Elsa

doi:10.1186/1471-2202-13-143

Cited by 32 publications

(32 citation statements)

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“…As recently reviewed [28], [29], the cellular effects of TNFα are mediated by two distinct receptor classes (TNFR1 and TNFR2).While TNFR1 is ubiquitously expressed and is canonically considered to be a pro-apoptotic signal in cell death pathways, TNFR2 expression is restricted to immune cells like microglia and macrophages, neurons and oligodendrocytes. In view of previous reports that neuroinflammation might be contributory to sensitize neurons in migraine attacks [9], [18], [30], [31], we first investigated whether mouse trigeminal ganglion neurons could respond to TNFα as evidenced by their expression of the TNFα receptor TNFR2 ([32]; Fig. 1A, B).…”

Section: Resultsmentioning

confidence: 99%

“…As P2X3 receptors in the brain and spinal cord are almost exclusively expressed on sensory neurons that transfer nociceptive signals to higher centers [7], [8], unraveling the primary mechanism may have significant relevance to understanding the generation of migraine-relevant pain processes. Since extracellular ATP levels are usually low [9], P2X3 receptors are not continuously activated under basal conditions in WT sensory neurons. However, constitutively up-regulated P2X3 receptors as seen in R192Q KI sensory neurons, are responsive already after application of low doses of the selective agonist α,β-methyleneadenosine 5-triphosphate (α,β-meATP) [6].…”

Section: Introductionmentioning

confidence: 99%

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The Mechanism of Functional Up-Regulation of P2X3 Receptors of Trigeminal Sensory Neurons in a Genetic Mouse Model of Familial Hemiplegic Migraine Type 1 (FHM-1)

et al. 2013

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A knock-in (KI) mouse model of FHM-1 expressing the R192Q missense mutation of the Cacna1a gene coding for the α1 subunit of CaV2.1 channels shows, at the level of the trigeminal ganglion, selective functional up-regulation of ATP -gated P2X3 receptors of sensory neurons that convey nociceptive signals to the brainstem. Why P2X3 receptors are constitutively more responsive, however, remains unclear as their membrane expression and TRPV1 nociceptor activity are the same as in wildtype (WT) neurons. Using primary cultures of WT or KI trigeminal ganglia, we investigated whether soluble compounds that may contribute to initiating (or maintaining) migraine attacks, such as TNFα, CGRP, and BDNF, might be responsible for increasing P2X3 receptor responses. Exogenous application of TNFα potentiated P2X3 receptor-mediated currents of WT but not of KI neurons, most of which expressed both the P2X3 receptor and the TNFα receptor TNFR2. However, sustained TNFα neutralization failed to change WT or KI P2X3 receptor currents. This suggests that endogenous TNFα does not regulate P2X3 receptor responses. Nonetheless, on cultures made from both genotypes, exogenous TNFα enhanced TRPV1 receptor-mediated currents expressed by a few neurons, suggesting transient amplification of TRPV1 nociceptor responses. CGRP increased P2X3 receptor currents only in WT cultures, although prolonged CGRP receptor antagonism or BDNF neutralization reduced KI currents to WT levels. Our data suggest that, in KI trigeminal ganglion cultures, constitutive up-regulation of P2X3 receptors probably is already maximal and is apparently contributed by basal CGRP and BDNF levels, thereby rendering these neurons more responsive to extracellular ATP.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Mechanism of Functional Up-Regulation of P2X3 Receptors of Trigeminal Sensory Neurons in a Genetic Mouse Model of Familial Hemiplegic Migraine Type 1 (FHM-1)

et al. 2013

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“…Our western blot analysis suggested that TRPM2 protein is expressed in neurons in TG. However, we acknowledge that our SGC-enriched TG cultures might also contain other cell types such as Schwan cells and macrophages (Glenn et al, 1993; Franceschini et al, 2012). Thus, our study suggests novel mechanisms involving TRPM2, a sensor of oxidative stress, by which peripheral inflammation leads to the production of cytokines and chemokines in both neurons and non-neuronal cells including SGCs that envelop neurons.…”

Section: Discussionmentioning

confidence: 99%

The role of TRPM2 in hydrogen peroxide-induced expression of inflammatory cytokine and chemokine in rat trigeminal ganglia

Chung¹,

Asgar²,

Lee³

et al. 2015

Neuroscience

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Trigeminal ganglia (TG) contain neuronal cell bodies surrounded by satellite glial cells. Although peripheral injury is well known to induce changes in gene expression within sensory ganglia, detailed mechanisms whereby peripheral injury leads to gene expression within sensory ganglia are not completely understood. Reactive oxygen species (ROS) are an important modulator of hyperalgesia, but the role of ROS generated within sensory ganglia is unclear. Since ROS are known to affect transcription processes, ROS generated within sensory ganglia could directly influence gene expression and induce cellular changes at the soma level. In this study, we hypothesized that peripheral inflammation leads to cytokine and chemokine production and ROS generation within TG and that transient receptor potential melastatin (TRPM2), a well known oxidative sensor, contributes to ROS-induced gene regulation within TG. The masseter injection of complete Freund’s adjuvant (CFA) resulted in a significantly elevated level of ROS within TG of the inflamed side with a concurrent increase in cytokine expression in TG. Treatment of TG cultures with H2O2 significantly up-regulated mRNA and protein levels of cytokine/chemokine such as interleukin 6 (IL-6) and chemokine (C-X-C motif) ligand 2 (CXCL2). TRPM2 was expressed in both neurons and nonneuronal cells in TG, and pretreatment of TG cultures with 2-aminoethoxydiphenyl borate (2-APB), an inhibitor of TRPM2, or siRNA against TRPM2 attenuated H2O2-induced up-regulation of IL-6 and CXCL2. These results suggested that activation of TRPM2 could play an important role in the modulation of cytokine/chemokine expression within TG under oxidative stress and that such changes may contribute to amplification of nociceptive signals leading to pathological pain conditions.

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“…Furthermore, inflammatory cells like macrophages releasing TNFα can further upregulate P2X3 receptor activity (Franceschini et al, 2012, 2013). It is also noteworthy that human P2X3 receptors recover about twice faster than analogous rodent receptors (Pratt et al, 2005).…”

Section: Functional Role Of Desensitization Of P2x3 Receptorsmentioning

confidence: 99%

Desensitization properties of P2X3 receptors shaping pain signaling

Giniatullin

Nistri

2013

Front. Cell. Neurosci.

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ATP-gated P2X3 receptors are mostly expressed by nociceptive sensory neurons and participate in transduction of pain signals. P2X3 receptors show a combination of fast desensitization onset and slow recovery. Moreover, even low nanomolar agonist concentrations unable to evoke a response, can induce desensitization via a phenomenon called “high affinity desensitization.” We have also observed that recovery from desensitization is agonist-specific and can range from seconds to minutes. The recovery process displays unusually high temperature dependence. Likewise, recycling of P2X3 receptors in peri-membrane regions shows unexpectedly large temperature sensitivity. By applying kinetic modeling, we have previously shown that desensitization characteristics of P2X3 receptor are best explained with a cyclic model of receptor operation involving three agonist molecules binding a single receptor and that desensitization is primarily developing from the open receptor state. Mutagenesis experiments suggested that desensitization depends on a certain conformation of the ATP binding pocket and on the structure of the transmembrane domains forming the ion pore. Further molecular determinants of desensitization have been identified by mutating the intracellular N- and C-termini of P2X3 receptor. Unlike other P2X receptors, the P2X3 subtype is facilitated by extracellular calcium that acts via specific sites in the ectodomain neighboring the ATP binding pocket. Thus, substitution of serine275 in this region (called “left flipper”) converts the natural facilitation induced by extracellular calcium to receptor inhibition. Given their strategic location in nociceptive neurons and unique desensitization properties, P2X3 receptors represent an attractive target for development of new analgesic drugs via promotion of desensitization aimed at suppressing chronic pain.

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Functional crosstalk in culture between macrophages and trigeminal sensory neurons of a mouse genetic model of migraine

Cited by 32 publications

References 34 publications

The Mechanism of Functional Up-Regulation of P2X3 Receptors of Trigeminal Sensory Neurons in a Genetic Mouse Model of Familial Hemiplegic Migraine Type 1 (FHM-1)

The Mechanism of Functional Up-Regulation of P2X3 Receptors of Trigeminal Sensory Neurons in a Genetic Mouse Model of Familial Hemiplegic Migraine Type 1 (FHM-1)

The role of TRPM2 in hydrogen peroxide-induced expression of inflammatory cytokine and chemokine in rat trigeminal ganglia

Desensitization properties of P2X3 receptors shaping pain signaling

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