Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2016

Open Access 01-12-2016 | Research

Immune response in the eye following epileptic seizures

Authors: Matilda Ahl, Una Avdic, Cecilia Skoug, Idrish Ali, Deepti Chugh, Ulrica Englund Johansson, Christine T Ekdahl

Published in: Journal of Neuroinflammation | Issue 1/2016

Login to get access

Abstract

Background

Epileptic seizures are associated with an immune response in the brain. However, it is not known whether it can extend to remote areas of the brain, such as the eyes. Hence, we investigated whether epileptic seizures induce inflammation in the retina.

Methods

Adult rats underwent electrically induced temporal status epilepticus, and the eyes were studied 6 h, 1, and 7 weeks later with biochemical and immunohistochemical analyses. An additional group of animals received CX3CR1 antibody intracerebroventricularly for 6 weeks after status epilepticus.

Results

Biochemical analyses and immunohistochemistry revealed no increased cell death and unaltered expression of several immune-related cytokines and chemokines as well as no microglial activation, 6 h post-status epilepticus compared to non-stimulated controls. At 1 week, again, retinal cytoarchitecture appeared normal and there was no cell death or micro- or macroglial reaction, apart from a small decrease in interleukin-10. However, at 7 weeks, even if the cytoarchitecture remained normal and no ongoing cell death was detected, the numbers of microglia were increased ipsi- and contralateral to the epileptic focus. The microglia remained within the synaptic layers but often in clusters and with more processes extending into the outer nuclear layer. Morphological analyses revealed a decrease in surveying and an increase in activated microglia. In addition, increased levels of the chemokine KC/GRO and cytokine interleukin-1β were found. Furthermore, macroglial activation was noted in the inner retina. No alterations in numbers of phagocytic cells, infiltrating macrophages, or vascular pericytes were observed. Post-synaptic density-95 cluster intensity was reduced in the outer nuclear layer, reflecting seizure-induced synaptic changes without disrupted cytoarchitecture in areas with increased microglial activation. The retinal gliosis was decreased by a CX3CR1 immune modulation known to reduce gliosis within epileptic foci, suggesting a common immunological reaction.

Conclusions

Our results are the first evidence that epileptic seizures induce an immune response in the retina. It has a potential to become a novel non-invasive tool for detecting brain inflammation through the eyes.
Literature
1.
2.
Kan AA, de Jager W, de Wit M, Heijnen C, van Zuiden M, Ferrier C, van Rijen P, Gosselaar P, Hessel E, van Nieuwenhuizen O, de Graan PN. Protein expression profiling of inflammatory mediators in human temporal lobe epilepsy reveals co-activation of multiple chemokines and cytokines. J Neuroinflammation. 2012;9:207.CrossRefPubMedPubMedCentral
3.
Ravizza T, Balosso S, Vezzani A. Inflammation and prevention of epileptogenesis. Neurosci Lett. 2011;497:223–30.CrossRefPubMed
4.
Crespel A, Coubes P, Rousset MC, Brana C, Rougier A, Rondouin G, Bockaert J, Baldy-Moulinier M, Lerner-Natoli M. Inflammatory reactions in human medial temporal lobe epilepsy with hippocampal sclerosis. Brain Res. 2002;952:159–69.CrossRefPubMed
5.
Legido A, Katsetos CD. Experimental studies in epilepsy: immunologic and inflammatory mechanisms. Semin Pediatr Neurol. 2014;21:197–206.CrossRefPubMed
6.
Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003;100:13632–7.CrossRefPubMedPubMedCentral
7.
Pernhorst K, Herms S, Hoffmann P, Cichon S, Schulz H, Sander T, Schoch S, Becker AJ, Grote A. TLR4, ATF-3 and IL8 inflammation mediator expression correlates with seizure frequency in human epileptic brain tissue. Seizure. 2013;22:675–8.CrossRefPubMed
8.
Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev. 2011;91:461–553.CrossRefPubMed
9.
Ekdahl CT, Kokaia Z, Lindvall O. Brain inflammation and adult neurogenesis: the dual role of microglia. Neuroscience. 2009;158:1021–9.CrossRefPubMed
10.
Crunelli V, Carmignoto G, Steinhauser C. Novel astrocyte targets: new avenues for the therapeutic treatment of epilepsy. Neuroscientist. 2015;21:62–83.CrossRefPubMedPubMedCentral
11.
Pittau F, Megevand P, Sheybani L, Abela E, Grouiller F, Spinelli L, Michel CM, Seeck M, Vulliemoz S. Mapping epileptic activity: sources or networks for the clinicians? Front Neurol. 2014;5:218.PubMedPubMedCentral
12.
Chugh D, Ali I, Bakochi A, Bahonjic E, Etholm L, Ekdahl CT. Alterations in brain inflammation, synaptic proteins, and adult hippocampal neurogenesis during epileptogenesis in mice lacking synapsin2. PLoS One. 2015;10:e0132366.CrossRefPubMedPubMedCentral
13.
Kolb H, Nelson R, Fernandez E, Jones B. The organization of the retina and visual systems. In: Anatomy and Physiology of the retina. University of Utah Health Science Center: Webvision; 2013.
14.
Karlstetter M, Scholz R, Rutar M, Wong WT, Provis JM, Langmann T. Retinal microglia: just bystander or target for therapy? Prog Retin Eye Res. 2014;45:30-57.
15.
Pfister F, Przybyt E, Harmsen MC, Hammes HP. Pericytes in the eye. Pflugers Arch. 2013;465:789–96.CrossRefPubMed
16.
Liu G, Meng C, Pan M, Chen M, Deng R, Lin L, Zhao L, Liu X. Isolation, purification, and cultivation of primary retinal microvascular pericytes: a novel model using rats. Microcirculation. 2014;21:478–89.CrossRefPubMed
17.
Mohapel P, Ekdahl CT, Lindvall O. Status epilepticus severity influences the long-term outcome of neurogenesis in the adult dentate gyrus. Neurobiol Dis. 2004;15:196–205.CrossRefPubMed
18.
Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol. 1972;32:281–94.CrossRefPubMed
19.
Ali I, Chugh D, Ekdahl CT. Role of fractalkine-CX3CR1 pathway in seizure-induced microglial activation, neurodegeneration, and neuroblast production in the adult rat brain. Neurobiol Dis. 2015;74:194–203.CrossRefPubMed
20.
Chugh D, Nilsson P, Afjei SA, Bakochi A, Ekdahl CT. Brain inflammation induces post-synaptic changes during early synapse formation in adult-born hippocampal neurons. Exp Neurol. 2013;250:176–88.CrossRefPubMed
21.
Soderstjerna E, Bauer P, Cedervall T, Abdshill H, Johansson F, Johansson UE. Silver and gold nanoparticles exposure to in vitro cultured retina—studies on nanoparticle internalization, apoptosis, oxidative stress, glial- and microglial activity. PLoS One. 2014;9:e105359.CrossRefPubMedPubMedCentral
22.
Ekdahl CT, Zhu C, Bonde S, Bahr BA, Blomgren K, Lindvall O. Death mechanisms in status epilepticus-generated neurons and effects of additional seizures on their survival. Neurobiol Dis. 2003;14:513–23.CrossRefPubMed
23.
Bonde S, Ekdahl CT, Lindvall O. Long-term neuronal replacement in adult rat hippocampus after status epilepticus despite chronic inflammation. Eur J Neurosci. 2006;23:965–74.CrossRefPubMed
24.
Eng LF. Glial fibrillary acidic protein (GFAP): the major protein of glial intermediate filaments in differentiated astrocytes. J Neuroimmunol. 1985;8:203–14.CrossRefPubMed
25.
26.
Norton WT, Aquino DA, Hozumi I, Chiu FC, Brosnan CF. Quantitative aspects of reactive gliosis: a review. Neurochem Res. 1992;17:877–85.CrossRefPubMed
27.
Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK, Streit WJ, Salafranca MN, Adhikari S, Thompson DA, et al. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci U S A. 1998;95:10896–901.CrossRefPubMedPubMedCentral
28.
29.
Thanos S. Sick photoreceptors attract activated microglia from the ganglion cell layer: a model to study the inflammatory cascades in rats with inherited retinal dystrophy. Brain Res. 1992;588:21–8.CrossRefPubMed
30.
Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA, Guiducci E, Dumas L, et al. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011;333:1456–8.CrossRefPubMed
31.
Roumier A, Bechade C, Poncer JC, Smalla KH, Tomasello E, Vivier E, Gundelfinger ED, Triller A, Bessis A. Impaired synaptic function in the microglial KARAP/DAP12-deficient mouse. J Neurosci. 2004;24:11421–8.CrossRefPubMed
32.
Koulen P, Fletcher EL, Craven SE, Bredt DS, Wassle H. Immunocytochemical localization of the postsynaptic density protein PSD-95 in the mammalian retina. J Neurosci. 1998;18:10136–49.PubMed
33.
London A, Benhar I, Schwartz M. The retina as a window to the brain-from eye research to CNS disorders. Nat Rev Neurol. 2013;9:44–53.CrossRefPubMed
34.
Cheung N, Mosley T, Islam A, Kawasaki R, Sharrett AR, Klein R, Coker LH, Knopman DS, Shibata DK, Catellier D, Wong TY. Retinal microvascular abnormalities and subclinical magnetic resonance imaging brain infarct: a prospective study. Brain. 2010;133:1987–93.CrossRefPubMedPubMedCentral
35.
Kaur M, Saxena R, Singh D, Behari M, Sharma P, Menon V. Correlation between structural and functional retinal changes in Parkinson disease. J Neuroophthalmol. 2015;35:254-258.
36.
Ragauskas S, Leinonen H, Puranen J, Ronkko S, Nymark S, Gurevicius K, Lipponen A, Kontkanen O, Puolivali J, Tanila H, Kalesnykas G. Early retinal function deficit without prominent morphological changes in the R6/2 mouse model of Huntington’s disease. PLoS One. 2014;9:e113317.CrossRefPubMedPubMedCentral
37.
Edwards MM, Rodriguez JJ, Gutierrez-Lanza R, Yates J, Verkhratsky A, Lutty GA. Retinal macroglia changes in a triple transgenic mouse model of Alzheimer’s disease. Exp Eye Res. 2014;127:252–60.CrossRefPubMedPubMedCentral
38.
Blanks JC, Schmidt SY, Torigoe Y, Porrello KV, Hinton DR, Blanks RH. Retinal pathology in Alzheimer’s disease. II. Regional neuron loss and glial changes in GCL. Neurobiol Aging. 1996;17:385–95.CrossRefPubMed
39.
Hill JM, Dua P, Clement C, Lukiw WJ. An evaluation of progressive amyloidogenic and pro-inflammatory change in the primary visual cortex and retina in Alzheimer’s disease (AD). Front Neurosci. 2014;8:347.CrossRefPubMedPubMedCentral
40.
Taylor L, Arner K, Ghosh F. First responders: dynamics of pre-gliotic Muller cell responses in the isolated adult rat retina. Curr Eye Res. 2014;40:1-16.
41.
Gorter JA, van Vliet EA, Aronica E, Breit T, Rauwerda H, da Silva FH, Wadman WJ. Potential new antiepileptogenic targets indicated by microarray analysis in a rat model for temporal lobe epilepsy. J Neurosci. 2006;26:11083–110.
42.
43.
Makita J, Hosoya K, Zhang P, Kador PF. Response of rat retinal capillary pericytes and endothelial cells to glucose. J Ocul Pharmacol Ther. 2011;27:7–15.CrossRefPubMedPubMedCentral
44.
45.
Buzney SM, Massicotte SJ, Hetu N, Zetter BR. Retinal vascular endothelial cells and pericytes. Differential growth characteristics in vitro. Invest Ophthalmol Vis Sci. 1983;24:470–80.PubMed
46.
von Tell D, Armulik A, Betsholtz C. Pericytes and vascular stability. Exp Cell Res. 2006;312:623–9.CrossRef
47.
Yamagishi S, Imaizumi T. Pericyte biology and diseases. Int J Tissue React. 2005;27:125–35.PubMed
48.
Berdahl JP, Fautsch MP, Stinnett SS, Allingham RR. Intracranial pressure in primary open angle glaucoma, normal tension glaucoma, and ocular hypertension: a case-control study. Invest Ophthalmol Vis Sci. 2008;49:5412–8.CrossRefPubMedPubMedCentral
49.
50.
Pang JJ, Frankfort BJ, Gross RL, Wu SM. Elevated intraocular pressure decreases response sensitivity of inner retinal neurons in experimental glaucoma mice. Proc Natl Acad Sci U S A. 2015;112:2593–8.CrossRefPubMedPubMedCentral
51.
Park HY, Kim JH, Park CK. Alterations of the synapse of the inner retinal layers after chronic intraocular pressure elevation in glaucoma animal model. Mol Brain. 2014;7:53.CrossRefPubMedPubMedCentral
52.
Pogue AI, Hill JM, Lukiw WJ. MicroRNA (miRNA): sequence and stability, viroid-like properties, and disease association in the CNS. Brain Res. 2014;1584:73–9.CrossRefPubMed
53.
Fukuda T, Oguni H, Yanagaki S, Fukuyama Y, Kogure M, Shimizu H, Oda M. Chronic localized encephalitis (Rasmussen’s syndrome) preceded by ipsilateral uveitis: a case report. Epilepsia. 1994;35:1328–31.CrossRefPubMed
54.
Fuhrmann M, Bittner T, Jung CK, Burgold S, Page RM, Mitteregger G, Haass C, LaFerla FM, Kretzschmar H, Herms J. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat Neurosci. 2010;13:411–3.CrossRefPubMedPubMedCentral
55.
Noda M, Doi Y, Liang J, Kawanokuchi J, Sonobe Y, Takeuchi H, Mizuno T, Suzumura A. Fractalkine attenuates excito-neurotoxicity via microglial clearance of damaged neurons and antioxidant enzyme heme oxygenase-1 expression. J Biol Chem. 2011;286:2308–19.CrossRefPubMed
56.
Yeo SI, Kim JE, Ryu HJ, Seo CH, Lee BC, Choi IG, Kim DS, Kang TC. The roles of fractalkine/CX3CR1 system in neuronal death following pilocarpine-induced status epilepticus. J Neuroimmunol. 2011;234:93–102.CrossRefPubMed
57.
Roseti C, Fucile S, Lauro C, Martinello K, Bertollini C, Esposito V, Mascia A, Catalano M, Aronica E, Limatola C, Palma E Fractalkine/CX3CL1 modulates GABAA currents in human temporal lobe epilepsy. Epilepsia. 2013;54:1834–44.CrossRefPubMed
58.
Combadiere C, Feumi C, Raoul W, Keller N, Rodero M, Pezard A, Lavalette S, Houssier M, Jonet L, Picard E, et al. CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration. J Clin Invest. 2007;117:2920–8.CrossRefPubMedPubMedCentral
59.
Bosco A, Romero CO, Breen KT, Chagovetz AA, Steele MR, Ambati BK, Vetter ML. Neurodegeneration severity can be predicted from early microglia alterations monitored in vivo in a mouse model of chronic glaucoma. Dis Model Mech. 2015;8:443–55.CrossRefPubMedPubMedCentral
60.
Wang K, Peng B, Lin B. Fractalkine receptor regulates microglial neurotoxicity in an experimental mouse glaucoma model. Glia. 2014;62:1943–54.CrossRefPubMed
61.
62.
Dutca LM, Stasheff SF, Hedberg-Buenz A, Rudd DS, Batra N, Blodi FR, Yorek MS, Yin T, Shankar M, Herlein JA, et al. Early detection of subclinical visual damage after blast-mediated TBI enables prevention of chronic visual deficit by treatment with P7C3-S243. Invest Ophthalmol Vis Sci. 2014;55:8330–41.CrossRefPubMed
63.
Thompson S, Blodi FR, Lee S, Welder CR, Mullins RF, Tucker BA, Stasheff SF, Stone EM. Photoreceptor cells with profound structural deficits can support useful vision in mice. Invest Ophthalmol Vis Sci. 2014;55:1859–66.CrossRefPubMedPubMedCentral
Metadata
Title
Immune response in the eye following epileptic seizures
Authors
Matilda Ahl
Una Avdic
Cecilia Skoug
Idrish Ali
Deepti Chugh
Ulrica Englund Johansson
Christine T Ekdahl
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-016-0618-3

Other articles of this Issue 1/2016

Journal of Neuroinflammation 1/2016 Go to the issue

Research

Anthocyanins abrogate glutamate-induced AMPK activation, oxidative stress, neuroinflammation, and neurodegeneration in postnatal rat brain

Research

Cellular investigations with human antibodies associated with the anti-IgLON5 syndrome

Research

Resveratrol suppresses glial activation and alleviates trigeminal neuralgia via activation of AMPK

Research

Sustained TNF production by central nervous system infiltrating macrophages promotes progressive autoimmune encephalomyelitis

Research

Complement-independent retinal pathology produced by intravitreal injection of neuromyelitis optica immunoglobulin G

Research

Type I Interferon response in olfactory bulb, the site of tick-borne flavivirus accumulation, is primarily regulated by IPS-1