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

BMC Neuroscience

Elsa Fabbretti²  Andrea Nistri⁴  Arn MJM van den Maagdenberg¹  Tanja Bele²  Asha Nair⁴  Alessia Franceschini³ 

[1] Departments of Human Genetics & Neurology, Leiden University Medical Centre, Leiden, RC, 2300, The Netherlands;Center for Biomedical Sciences and Engineering, University of Nova Gorica, Nova Gorica, SI-5000, Slovenia;Present address: Department of Experimental and Diagnostic Medicine, Section of General Pathology, University of Ferrara, Ferrara, Italy;Department of Neuroscience and Italian Institute of Technology Unit, International School for Advanced Studies (SISSA), Via Bonomea 265, Trieste, 34136, Italy

关键词: Sensitization;    ATP;    Neuroinflammation;    Pain;    Purinergic receptor;    P2X3 receptor;   

Others  :  1140703
DOI  :  10.1186/1471-2202-13-143

 received in 2012-05-29, accepted in 2012-10-31,  发布年份 2012

【 摘 要 】

Background

Enhanced activity of trigeminal ganglion neurons is thought to underlie neuronal sensitization facilitating the onset of chronic pain attacks, including migraine. Recurrent headache attacks might establish a chronic neuroinflammatory ganglion profile contributing to the hypersensitive phenotype. Since it is difficult to study this process in vivo, we investigated functional crosstalk between macrophages and sensory neurons in primary cultures from trigeminal sensory ganglia of wild-type (WT) or knock-in (KI) mice expressing the Cacna1a gene mutation (R192Q) found in familial hemiplegic migraine-type 1. After studying the number and morphology of resident macrophages in culture, the consequences of adding host macrophages on macrophage phagocytosis and membrane currents mediated by pain-transducing P2X3 receptors on sensory neurons were examined.

Results

KI ganglion cultures constitutively contained a larger number of active macrophages, although no difference in P2X3 receptor expression was found. Co-culturing WT or KI ganglia with host macrophages (active as much as resident cells) strongly stimulated single cell phagocytosis. The same protocol had no effect on P2X3 receptor expression in WT or KI co-cultures, but it largely enhanced WT neuron currents that grew to the high amplitude constitutively seen for KI neurons. No further potentiation of KI neuronal currents was observed.

Conclusions

Trigeminal ganglion cultures from a genetic mouse model of migraine showed basal macrophage activation together with enhanced neuronal currents mediated by P2X3 receptors. This phenotype could be replicated in WT cultures by adding host macrophages, indicating an important functional crosstalk between macrophages and sensory neurons.

【 授权许可】

   
2012 Franceschini et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]van den Maagdenberg AMJM, Haan J, Terwindt GM, Ferrari MD: Migraine: gene mutations and functional consequences. Curr Opin Neurol 2007, 20:299-305.
• [2]May A: New insights into headache: an update on functional and structural imaging findings. Nat Rev Neurol 2009, 5:199-209.
• [3]Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SMG, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GB, Hofker MH, Ferrari MD, Frants RR: Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996, 87:543-552.
• [4]van den Maagdenberg AM, Pietrobon D, Pizzorusso T, Kaja S, Broos LA, Cesetti T, van de Ven RC, Tottene A, van der Kaa J, Plomp JJ, Frants RR, Ferrari MD: A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 2004, 41:701-710.
• [5]Tottene A, Fellin T, Pagnutti S, Luvisetto S, Striessnig J, Fletcher C, Pietrobon D: Familial hemiplegic migraine mutations increase Ca2+ influx through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons. Proc Natl Acad Sci USA 2002, 99:13284-13289.
• [6]van den Maagdenberg AMJM, Pizzorusso T, Kaja S, Terpolilli N, Shapovalova M, Hoebeek FE, Barrett CF, Gherardini L, van de Ven RCG, Todorov B, Broos LAM, Tottene A, Gao Z, Fodor M, De Zeeuw CI, Frants RR, Plesnila N, Plomp JJ, Pietrobon D, Ferrari MD: High cortical spreading depression susceptibility and migraine-associated symptoms in CaV2.1 S218L mice. Ann Neurol 2010, 67:85-98.
• [7]Tottene A, Conti R, Fabbro A, Vecchia D, Shapovalova M, Santello M, van den Maagdenberg AM, Ferrari MD, Pietrobon D: Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading depression in Ca(v)2.1 knockin migraine mice. Neuron 2009, 61:762-773.
• [8]Lauritzen M: Pathophysiology of the migraine aura. The spreading depression theory. Brain 1994, 117:199-210.
• [9]Nair A, Simonetti M, Birsa N, Ferrari MD, van den Maagdenberg AM, Giniatullin R, Nistri A, Fabbretti E: Familial hemiplegic migraine CaV2.1 channel mutation R192Q enhances ATP-gated P2X3 receptor activity of mouse sensory ganglion neurons mediating trigeminal pain. Mol Pain 2010, 6:48. BioMed Central Full Text
• [10]Giniatullin R, Nistri A, Fabbretti E: Molecular mechanisms of sensitization of pain-transducing P2X3 receptors by the migraine mediators CGRP and NGF. Mol Neurobiol 2008, 37:83-90.
• [11]Ceruti S, Villa G, Fumagalli M, Colombo L, Magni G, Zanardelli M, Fabbretti E, Verderio C, van den Maagdenberg AMJM, Nistri A, Abbracchio MP: Calcitonin gene-related peptide-mediated enhancement of purinergic neuron/glia communication by the algogenic factor bradykinin in mouse trigeminal ganglia from wild-type and R192Q CaV2.1 knock-in mice: implications for basic mechanisms of migraine pain. J Neurosci 2011, 31:3638-3649.
• [12]Moskowitz MA: Basic mechanisms in vascular headache. Neurol Clin 1990, 8:801-815.
• [13]Moskowitz MA: Neurogenic inflammation in the pathophysiology and treatment of migraine. Neurology 1993, 43(Suppl 3):S16-S20.
• [14]Hamed SA: The vascular risk associations with migraine: Relation to migraine susceptibility and progression. Atherosclerosis 2009, 205:15-22.
• [15]Pietrobon D, Striessnig J: Neurobiology of migraine. Nat Rev Neurosci 2003, 4:386-398.
• [16]David S, Kroner A: Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 2011, 12:388-399.
• [17]Simonetti M, Fabbro A, D’Arco M, Zweyer M, Nistri A, Giniatullin R, Fabbretti E: Comparison of P2X and TRPV1 receptors in ganglia or primary culture of trigeminal neurons and their modulation by NGF or serotonin. Mol Pain 2006, 2:11. BioMed Central Full Text
• [18]Ray A, Dittel BN: Isolation of Mouse Peritoneal Cavity Cells. J Vis Exp 2010, 35:1488.
• [19]Imai Y, Ibata I, Ito D, Ohsawa K, Kohsaka S: A novel gene Iba1 in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage. Biochem Biophys Res Commun 1996, 224:855-862.
• [20]Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, Kohsaka S: Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res Mol Brain Res 1998, 57:1-9.
• [21]Harrigan TJ, Abdullaev IF, Jourd’heuil D, Mongin AA: Activation of microglia with zymosan promotes excitatory amino acid release via volume-regulated anion channels: the role of NADPH oxidases. J Neurochem 2008, 106:2449-2462.
• [22]Färber K, Cheung G, Mitchell D, Wallis R, Weihe E, Schwaeble W, Kettenmann H: C1q, the recognition subcomponent of the classical pathway of complement, drives microglial activation. J Neurosci Res 2009, 87:644-652.
• [23]D’Arco M, Giniatullin R, Simonetti M, Fabbro A, Nair A, Nistri A, Fabbretti E: Neutralization of nerve growth factor induces plasticity of ATP-sensitive P2X3 receptors of nociceptive trigeminal ganglion neurons. J Neurosci 2007, 27:8190-8201.
• [24]Etheredge JA, Murchison D, Abbott LC, Griffith WH: Functional compensation by other voltage-gated Ca2+ channels in mouse basal forebrain neurons with CaV2.1 mutations. Brain Res 2007, 1140:105-119.
• [25]Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, Vandesompele J, Wittwer CT: The MIQE Guidelines: Minimum Information for Publication of Quantitative Real-Time PCR Experiments. Clin Chem 2009, 2009(55):611-622.
• [26]Seifert S, Pannell M, Uckert W, Färber K, Kettenmann H: Transmitter- and hormoneactivated Ca2+ responses in adult microglia/brain macrophages in situ recorded after viral transduction of a recombinant Ca2+ sensor. Cell Calcium 2011, 49:365-375.
• [27]Villa G, Ceruti S, Zanardelli M, Magni G, Jasmin L, Ohara PT, Abbracchio MP: Temporomandibular joint inflammation activates glial and immune cells in both the trigeminal ganglia and in the spinal trigeminal nucleus. Mol Pain 2010, 6:89. BioMed Central Full Text
• [28]Fabbretti E, Nistri A: Regulation of P2X3 Receptor Structure and Function. CNS Neurol Disord Drug Targets 2012. Epub ahead of print
• [29]Franceschini A, Hullugundi SK, van den Maagdenberg AM, Nistri A, Fabbretti E: Effects of LPS on P2X3 receptors of trigeminal sensory neurons and macrophages from mice expressing the R192Q Cacna1a gene mutation of familial hemiplegic migraine-1. Purinergic Signal 2012. Epub ahead of print
• [30]Waeber C, Moskowitz MA: Migraine as an inflammatory disorder. Neurology 2005, 64(Suppl 2):S9-15.
• [31]Pietrobon D: CaV2.1 channelopathies. Pflugers Arch 2010, 460:375-393.
• [32]Burnstock G: Purinergic receptors and pain. Curr Pharm Des 2009, 15:1717-1735.
• [33]Sokolova E, Skorinkin A, Moiseev I, Agrachev A, Nistri A, Giniatullin R: Experimental and modeling studies of desensitization of P2X3 receptors. Mol Pharmacol 2006, 70:373-382.
• [34]Raddant AC, Russo AF: Calcitonin gene-related peptide in migraine: intersection of peripheral inflammation and central modulation. Expert Rev Mol Med. 2011, 13:e36.
• [35]Inoue K: The function of microglia through purinergic receptors: neuropathic pain and cytokine release. Pharmacol Ther 2006, 109:210-226.