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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2019

Open Access 01-12-2019 | Migraine | Research

Microglial NLRP3 inflammasome activation mediates IL-1β release and contributes to central sensitization in a recurrent nitroglycerin-induced migraine model

Authors: Wei He, Ting Long, Qi Pan, Shanshan Zhang, Yixin Zhang, Dunke Zhang, Guangcheng Qin, Lixue Chen, Jiying Zhou

Published in: Journal of Neuroinflammation | Issue 1/2019

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Abstract

Background

Central sensitization is an important mechanism of chronic migraine (CM) and is related to the inflammatory response of microglia. The NOD-like receptor protein 3 (NLRP3) inflammasome may regulate the inflammatory process of microglia in several neurological diseases, but its role in CM is largely unknown. Therefore, the aim of this study was to identify the precise role of microglial NLRP3 in CM.

Methods

An experimental CM mouse model was established by repeated intraperitoneal (i.p) injection with nitroglycerin (NTG). We evaluated the expression levels of NLRP3 and its downstream interleukin (IL)-1β protein in the trigeminal nucleus caudalis (TNC; which is a central area relevant to migraine pain) at different time points. To further examine the effects of the NLRP3 inflammasome pathway on central sensitization of CM, we examined MCC950, an NLRP3 inflammasome-specific inhibitor, and IL-1ra, an IL-1β antagonist, whether altered NTG-induced mechanical hyperalgesia of the periorbital area and hind paw. The effect of MCC950 and IL-1ra on c-Fos, phosphorylated extracellular signal-regulated kinase (p-ERK) and calcitonin gene-related peptide (CGRP) expression in the TNC were also analyzed. The cell localization of NLRP3 and IL-1β in the TNC was evaluated by immunofluorescence staining.

Results

Repeated NTG administration induced acute and chronic mechanical hyperalgesia and increased expression of NLRP3 and IL-1β. Blockade of NLRP3 or IL-1β reduced NTG-induced hyperalgesia, and this effect was accompanied by a significant inhibition of the NTG-induced increase in p-ERK, c-Fos and CGRP levels in the TNC. Immunofluorescence staining revealed that NLRP3 and IL-1β were mainly expressed in microglia in the TNC, and the IL-1β receptor, IL-1R, was mainly expressed in neurons in the TNC.

Conclusions

These results indicate that NLRP3 activation in the TNC participates in the microglial-neuronal signal by mediating the inflammatory response. This process contributes to the central sensitization observed in CM.
Appendix
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Literature
1.
Stovner L, Hagen K, Jensen R, Katsarava Z, Lipton R, Scher A, Steiner T, Zwart JA. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia. 2007;27:193–210.CrossRef
2.
Natoli JL, Manack A, Dean B, Butler Q, Turkel CC, Stovner L, Lipton RB. Global prevalence of chronic migraine: a systematic review. Cephalalgia. 2010;30:599–609.CrossRef
3.
Tfelt-Hansen P, Olesen J. Taking the negative view of current migraine treatments: the unmet needs. CNS Drugs. 2012;26:375–82.CrossRef
4.
Bernstein C, Burstein R. Sensitization of the trigeminovascular pathway: perspective and implications to migraine pathophysiology. J Clin Neurol. 2012;8:89–99.CrossRef
5.
Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10:895–926.CrossRef
6.
Xie YF, Zhang S, Chiang CY, Hu JW, Dostrovsky JO, Sessle BJ. Involvement of glia in central sensitization in trigeminal subnucleus caudalis (medullary dorsal horn). Brain Behav Immun. 2007;21:634–41.CrossRef
7.
Peng J, Gu N, Zhou L, EU B, Murugan M, Gan WB, Wu LJ. Microglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury. Nat Commun. 2016;7:12029.CrossRef
8.
Bartley J. Could glial activation be a factor in migraine? Med Hypotheses. 2009;72:255–7.CrossRef
9.
Long T, He W, Pan Q, Zhang S, Zhang Y, Liu C, Liu Q, Qin G, Chen L, Zhou J. Microglia P2X4 receptor contributes to central sensitization following recurrent nitroglycerin stimulation. J Neuroinflammation. 2018;15:245.CrossRef
10.
Sarchielli P, Alberti A, Baldi A, Coppola F, Rossi C, Pierguidi L, Floridi A, Calabresi P. Proinflammatory cytokines, adhesion molecules, and lymphocyte integrin expression in the internal jugular blood of migraine patients without aura assessed ictally. Headache. 2006;46:200–7.CrossRef
11.
De Corato A, Lisi L, Capuano A, Tringali G, Tramutola A, Navarra P, Dello RC. Trigeminal satellite cells express functional calcitonin gene-related peptide receptors, whose activation enhances interleukin-1beta pro-inflammatory effects. J Neuroimmunol. 2011;237:39–46.CrossRef
12.
Liu X, Quan N. Microglia and CNS interleukin-1: beyond immunological concepts. Front Neurol. 2018;9:8.CrossRef
13.
Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10:417–26.CrossRef
14.
Pan Y, Chen XY, Zhang QY, Kong LD. Microglial NLRP3 inflammasome activation mediates IL-1beta-related inflammation in prefrontal cortex of depressive rats. Brain Behav Immun. 2014;41:90–100.CrossRef
15.
Ma Q, Chen S, Hu Q, Feng H, Zhang JH, Tang J. NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage. Ann Neurol. 2014;75:209–19.CrossRef
16.
Gris D, Ye Z, Iocca HA, Wen H, Craven RR, Gris P, Huang M, Schneider M, Miller SD, Ting JP. NLRP3 plays a critical role in the development of experimental autoimmune encephalomyelitis by mediating Th1 and Th17 responses. J Immunol. 2010;185:974–81.CrossRef
17.
Goloncser F, Sperlagh B. Effect of genetic deletion and pharmacological antagonism of P2X7 receptors in a mouse animal model of migraine. J Headache Pain. 2014;15:24.CrossRef
18.
Rajamaki K, Nordstrom T, Nurmi K, Akerman KE, Kovanen PT, Oorni K, Eklund KK. Extracellular acidosis is a novel danger signal alerting innate immunity via the NLRP3 inflammasome. J Biol Chem. 2013;288:13410–9.CrossRef
19.
Yilmaz G, Surer H, Inan LE, Coskun O, Yucel D. Increased nitrosative and oxidative stress in platelets of migraine patients. Tohoku J Exp Med. 2007;211:23–30.CrossRef
20.
Bellezza I, Grottelli S, Costanzi E, Scarpelli P, Pigna E, Morozzi G, Mezzasoma L, Peirce MJ, Moresi V, Adamo S, Minelli A. Peroxynitrite activates the NLRP3 inflammasome cascade in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Mol Neurobiol. 2018;55:2350–61.CrossRef
21.
He Y, Hara H, Nunez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci. 2016;41:1012–21.CrossRef
22.
Sparaco M, Feleppa M, Lipton RB, Rapoport AM, Bigal ME. Mitochondrial dysfunction and migraine: evidence and hypotheses. Cephalalgia. 2006;26:361–72.CrossRef
23.
Abais JM, Xia M, Zhang Y, Boini KM, Li PL. Redox regulation of NLRP3 inflammasomes: ROS as trigger or effector? Antioxid Redox Signal. 2015;22:1111–29.CrossRef
24.
Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain. 1983;16:109–10.CrossRef
25.
Pradhan AA, Smith ML, McGuire B, Tarash I, Evans CJ, Charles A. Characterization of a novel model of chronic migraine. Pain. 2014;155:269–74.CrossRef
26.
Abraham J, Jang S, Godbout JP, Chen J, Kelley KW, Dantzer R, Johnson RW. Aging sensitizes mice to behavioral deficits induced by central HIV-1 gp120. Neurobiol Aging. 2008;29:614–21.CrossRef
27.
Abraham J, Johnson RW. Central inhibition of interleukin-1beta ameliorates sickness behavior in aged mice. Brain Behav Immun. 2009;23:396–401.CrossRef
28.
Dempsey C, Rubio AA, Bryson KJ, Finucane O, Larkin C, Mills EL, Robertson A, Cooper MA, O'Neill L, Lynch MA. Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-beta and cognitive function in APP/PS1 mice. Brain Behav Immun. 2017;61:306–16.CrossRef
29.
Coll RC, Robertson AAB, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015;21:248–55.CrossRef
30.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 2001;25:402–8.CrossRef
31.
Pinskiy V, Tolpygo AS, Jones J, Weber K, Franciotti N, Mitra PP. A low-cost technique to cryo-protect and freeze rodent brains, precisely aligned to stereotaxic coordinates for whole-brain cryosectioning. J Neurosci Methods. 2013;218:206–13.CrossRef
32.
Gao YJ, Ji RR. c-Fos and pERK, which is a better marker for neuronal activation and central sensitization after noxious stimulation and tissue injury? Open Pain J. 2009;2:11–7.CrossRef
33.
Riesco N, Cernuda-Morollon E, Pascual J. Neuropeptides as a marker for chronic headache. Curr Pain Headache R. 2017;21(18).
34.
Tipton AF, Tarash I, McGuire B, Charles A, Pradhan AA. The effects of acute and preventive migraine therapies in a mouse model of chronic migraine. Cephalalgia. 2016;36:1048–56.CrossRef
35.
Farajdokht F, Mohaddes G, Shanehbandi D, Karimi P, Babri S. Ghrelin attenuated hyperalgesia induced by chronic nitroglycerin: CGRP and TRPV1 as targets for migraine management. Cephalalgia. 2018;38:1716–30.CrossRef
36.
Ben AM, Tipton AF, Bertels Z, Gandhi R, Moye LS, Novack M, Bennett BM, Wang Y, Litosh V, Lee SH, et al. Soluble guanylyl cyclase is a critical regulator of migraine-associated pain. Cephalalgia. 2018;38:1471–84.CrossRef
37.
Kim SJ, Yeo JH, Yoon SY, Kwon SG, Lee JH, Beitz AJ, Roh DH. Differential development of facial and hind paw allodynia in a nitroglycerin-induced mouse model of chronic migraine: role of capsaicin sensitive primary afferents. Biol Pharm Bull. 2018;41:172–81.CrossRef
38.
Burstein R. Deconstructing migraine headache into peripheral and central sensitization. Pain. 2001;89:107–10.CrossRef
39.
Greco R, Demartini C, Zanaboni AM, Redavide E, Pampalone S, Toldi J, Fulop F, Blandini F, Nappi G, Sandrini G, et al. Effects of kynurenic acid analogue 1 (KYNA-A1) in nitroglycerin-induced hyperalgesia: targets and anti-migraine mechanisms. Cephalalgia. 2017;37:1272–84.CrossRef
40.
Cady RJ, Glenn JR, Smith KM, Durham PL. Calcitonin gene-related peptide promotes cellular changes in trigeminal neurons and glia implicated in peripheral and central sensitization. Mol Pain. 2011;7:94.CrossRef
41.
Iyengar S, Ossipov MH, Johnson KW. The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine. Pain. 2017;158:543–59.CrossRef
42.
Jia M, Wu C, Gao F, Xiang H, Sun N, Peng P, Li J, Yuan X, Li H, Meng X, et al. Activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel-induced neuropathic pain. Mol Pain. 2017;13:2071443716.CrossRef
43.
Richter F, Eitner A, Leuchtweis J, Bauer R, Lehmenkuhler A, Schaible H. Effects of interleukin-1β on cortical spreading depolarization and cerebral vasculature. J Cerebr Blood F Met. 2017;37:1791–802.CrossRef
44.
Cai Y, Kong H, Pan YB, Jiang L, Pan XX, Hu L, Qian YN, Jiang CY, Liu WT. Procyanidins alleviates morphine tolerance by inhibiting activation of NLRP3 inflammasome in microglia. J Neuroinflammation. 2016;13:53.CrossRef
45.
Chen L, Li X, Huang L, Wu Q, Chen L, Wan Q. Chemical stimulation of the intracranial dura activates NALP3 inflammasome in trigeminal ganglia neurons. Brain Res. 2014;1566:1–11.CrossRef
46.
Munoz-Planillo R, Kuffa P, Martinez-Colon G, Smith BL, Rajendiran TM, Nunez G. K(+) efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity. 2013;38:1142–53.CrossRef
47.
Buisman HP, Steinberg TH, Fischbarg J, Silverstein SC, Vogelzang SA, Ince C, Ypey DL, Leijh PC. Extracellular ATP induces a large nonselective conductance in macrophage plasma membranes. Proc Natl Acad Sci U S A. 1988;85:7988–92.CrossRef
48.
Raddant AC, Russo AF. Reactive oxygen species induce procalcitonin expression in trigeminal ganglia glia. Headache. 2014;54:472–84.CrossRef
49.
Colombo B, Saraceno L, Comi G. Riboflavin and migraine: the bridge over troubled mitochondria. Neurol Sci. 2014;35(Suppl 1):141–4.CrossRef
50.
Shaik MM, Gan SH. Vitamin supplementation as possible prophylactic treatment against migraine with aura and menstrual migraine. Biomed Res Int. 2015;2015:469529.PubMedPubMedCentral
51.
Brough D, Rothwell NJ, Allan SM. Interleukin-1 as a pharmacological target in acute brain injury. Exp Physiol. 2015;100:1488–94.CrossRef
Metadata
Title
Microglial NLRP3 inflammasome activation mediates IL-1β release and contributes to central sensitization in a recurrent nitroglycerin-induced migraine model
Authors
Wei He
Ting Long
Qi Pan
Shanshan Zhang
Yixin Zhang
Dunke Zhang
Guangcheng Qin
Lixue Chen
Jiying Zhou
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2019
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-019-1459-7

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