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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2016

Open Access 01-12-2016 | Research

Nogo receptor complex expression dynamics in the inflammatory foci of central nervous system experimental autoimmune demyelination

Authors: Paschalis Theotokis, Olga Touloumi, Roza Lagoudaki, Evangelia Nousiopoulou, Evangelia Kesidou, Spyridon Siafis, Theodoros Tselios, Athanasios Lourbopoulos, Dimitrios Karacostas, Nikolaos Grigoriadis, Constantina Simeonidou

Published in: Journal of Neuroinflammation | Issue 1/2016

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Abstract

Background

Nogo-A and its putative receptor NgR are considered to be among the inhibitors of axonal regeneration in the CNS. However, few studies so far have addressed the issue of local NgR complex multilateral localization within inflammation in an MS mouse model of autoimmune demyelination.

Methods

Chronic experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice. Analyses were performed on acute (days 18–22) and chronic (day 50) time points and compared to controls. The temporal and spatial expression of the Nogo receptor complex (NgR and coreceptors) was studied at the spinal cord using epifluorescent and confocal microscopy or real-time PCR. Data are expressed as cells/mm2, as mean % ± SEM, or as arbitrary units of integrated density.

Results

Animals developed a moderate to severe EAE without mortality, followed by a progressive, chronic clinical course. NgR complex spatial expression varied during the main time points of EAE. NgR with coreceptors LINGO-1 and TROY was increased in the spinal cord in the acute phase whereas LINGO-1 and p75 signal seemed to be dominant in the chronic phase, respectively. NgR was detected on gray matter NeuN+ neurons of the spinal cord, within the white matter inflammatory foci (14.2 ± 4.3 % NgR+ inflammatory cells), and found to be colocalized with GAP-43+ axonal growth cones while no β-TubIII+, SMI-32+, or APP+ axons were found as NgR+. Among the NgR+ inflammatory cells, 75.6 ± 9.0 % were microglial/macrophages (lectin+), 49.6 ± 14.2 % expressed CD68 (phagocytic ED1+ cells), and no cells were Mac-3+. Of these macrophages/monocytes, only Arginase-1+/NgR+ but not iNOS+/NgR+ were present in lesions both in acute and chronic phases.

Conclusions

Our data describe in detail the expression of the Nogo receptor complex within the autoimmune inflammatory foci and suggest a possible immune action for NgR apart from the established inhibitory one on axonal growth. Its expression by inflammatory macrophages/monocytes could signify a possible role of these cells on axonal guidance and clearance of the lesioned area during inflammatory demyelination.
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Literature
1.
Fournier AE, GrandPre T, Strittmatter SM. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature. 2001;409:341–6.CrossRefPubMed
2.
Wang KC, Kim JA, Sivasankaran R, Segal R, He Z. P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature. 2002;420:74–8.CrossRefPubMed
3.
Park JB, Yiu G, Kaneko S, Wang J, Chang J, He XL, Garcia KC, He Z. A TNF receptor family member, TROY, is a coreceptor with Nogo receptor in mediating the inhibitory activity of myelin inhibitors. Neuron. 2005;45:345–51.CrossRefPubMed
4.
Mi S, Lee X, Shao Z, Thill G, Ji B, Relton J, Levesque M, Allaire N, Perrin S, Sands B, et al. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat Neurosci. 2004;7:221–8.CrossRefPubMed
5.
Ahmed Z, Douglas MR, John G, Berry M, Logan A. AMIGO3 is an NgR1/p75 co-receptor signalling axon growth inhibition in the acute phase of adult central nervous system injury. PLoS One. 2013;8:e61878.CrossRefPubMedPubMedCentral
6.
Satoh J, Onoue H, Arima K, Yamamura T. Nogo-A and nogo receptor expression in demyelinating lesions of multiple sclerosis. J Neuropathol Exp Neurol. 2005;64:129–38.CrossRefPubMed
7.
Wang X, Chun SJ, Treloar H, Vartanian T, Greer CA, Strittmatter SM. Localization of Nogo-A and Nogo-66 receptor proteins at sites of axon-myelin and synaptic contact. J Neurosci. 2002;22:5505–15.PubMed
8.
Domeniconi M, Cao Z, Spencer T, Sivasankaran R, Wang K, Nikulina E, Kimura N, Cai H, Deng K, Gao Y, et al. Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth. Neuron. 2002;35:283–90.CrossRefPubMed
9.
Wang KC, Koprivica V, Kim JA, Sivasankaran R, Guo Y, Neve RL, He Z. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature. 2002;417:941–4.CrossRefPubMed
10.
Barton WA, Liu BP, Tzvetkova D, Jeffrey PD, Fournier AE, Sah D, Cate R, Strittmatter SM, Nikolov DB. Structure and axon outgrowth inhibitor binding of the Nogo-66 receptor and related proteins. EMBO J. 2003;22:3291–302.CrossRefPubMedPubMedCentral
11.
12.
Shao Z, Browning JL, Lee X, Scott ML, Shulga-Morskaya S, Allaire N, Thill G, Levesque M, Sah D, McCoy JM, et al. TAJ/TROY, an orphan TNF receptor family member, binds Nogo-66 receptor 1 and regulates axonal regeneration. Neuron. 2005;45:353–9.CrossRefPubMed
13.
Mosyak L, Wood A, Dwyer B, Buddha M, Johnson M, Aulabaugh A, Zhong X, Presman E, Benard S, Kelleher K, et al. The structure of the Lingo-1 ectodomain, a module implicated in central nervous system repair inhibition. J Biol Chem. 2006;281:36378–90.CrossRefPubMed
14.
Meininger V, Pradat PF, Corse A, Al-Sarraj S, Rix Brooks B, Caress JB, Cudkowicz M, Kolb SJ, Lange D, Leigh PN, et al. Safety, pharmacokinetic, and functional effects of the Nogo-A monoclonal antibody in amyotrophic lateral sclerosis: a randomized, first-in-human clinical trial. PLoS One. 2014;9:e97803.CrossRefPubMedPubMedCentral
15.
Tran JQ, Rana J, Barkhof F, Melamed I, Gevorkyan H, Wattjes MP, de Jong R, Brosofsky K, Ray S, Xu L, et al. Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033. Neurol Neuroimmunol Neuroinflamm. 2014;1:e18.CrossRefPubMedPubMedCentral
16.
Litwak SA, Payne NL, Campanale N, Ozturk E, Lee JY, Petratos S, Siatskas C, Bakhuraysah M, Bernard CC. Nogo-receptor 1 deficiency has no influence on immune cell repertoire or function during experimental autoimmune encephalomyelitis. PLoS One. 2013;8:e82101.CrossRefPubMedPubMedCentral
17.
Steinbach K, McDonald CL, Reindl M, Schweigreiter R, Bandtlow C, Martin R. Nogo-receptors NgR1 and NgR2 do not mediate regulation of CD4 T helper responses and CNS repair in experimental autoimmune encephalomyelitis. PLoS One. 2011;6:e26341.CrossRefPubMedPubMedCentral
18.
Pourabdolhossein F, Mozafari S, Morvan-Dubois G, Mirnajafi-Zadeh J, Lopez-Juarez A, Pierre-Simons J, Demeneix BA, Javan M. Nogo receptor inhibition enhances functional recovery following lysolecithin-induced demyelination in mouse optic chiasm. PLoS One. 2014;9:e106378.CrossRefPubMedPubMedCentral
19.
Cui Z, Kang J, Hu D, Zhou J, Wang Y. Oncomodulin/truncated protamine-mediated Nogo-66 receptor small interference RNA delivery promotes axon regeneration in retinal ganglion cells. Mol Cells. 2014;37:613–9.CrossRefPubMedPubMedCentral
20.
Takahashi K, Rochford CD, Neumann H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med. 2005;201:647–57.CrossRefPubMedPubMedCentral
21.
David S, Fry EJ, Lopez-Vales R. Novel roles for Nogo receptor in inflammation and disease. Trends Neurosci. 2008;31:221–6.CrossRefPubMed
22.
Fry EJ, Ho C, David S. A role for Nogo receptor in macrophage clearance from injured peripheral nerve. Neuron. 2007;53:649–62.CrossRefPubMed
23.
Theotokis P, Lourbopoulos A, Touloumi O, Lagoudaki R, Kofidou E, Nousiopoulou E, Poulatsidou KN, Kesidou E, Tascos N, Spandou E, Grigoriadis N. Time course and spatial profile of Nogo-A expression in experimental autoimmune encephalomyelitis in C57BL/6 mice. J Neuropathol Exp Neurol. 2012;71:907–20.CrossRefPubMed
24.
Theotokis P, Kleopa KA, Touloumi O, Lagoudaki R, Lourbopoulos A, Nousiopoulou E, Kesidou E, Poulatsidou KN, Dardiotis E, Hadjigeorgiou G, et al. Connexin43 and connexin47 alterations after neural precursor cells transplantation in experimental autoimmune encephalomyelitis. Glia. 2015;63:1772–83.CrossRefPubMed
25.
de Luca LE, Pikor NB, O’Leary J, Galicia-Rosas G, Ward LA, Defreitas D, Finlay TM, Ousman SS, Osborne LR, Gommerman JL. Substrain differences reveal novel disease-modifying gene candidates that alter the clinical course of a rodent model of multiple sclerosis. J Immunol. 2010;184:3174–85.CrossRef
26.
Gur-Wahnon D, Mizrachi T, Maaravi-Pinto FY, Lourbopoulos A, Grigoriadis N, Higazi AA, Brenner T. The plasminogen activator system: involvement in central nervous system inflammation and a potential site for therapeutic intervention. J Neuroinflammation. 2013;10:124.CrossRefPubMedPubMedCentral
27.
Lourbopoulos A, Grigoriadis N, Lagoudaki R, Touloumi O, Polyzoidou E, Mavromatis I, Tascos N, Breuer A, Ovadia H, Karussis D, et al. Administration of 2-arachidonoylglycerol ameliorates both acute and chronic experimental autoimmune encephalomyelitis. Brain Res. 2011;1390:126–41.CrossRefPubMed
28.
Ahn M, Yang W, Kim H, Jin JK, Moon C, Shin T. Immunohistochemical study of arginase-1 in the spinal cords of Lewis rats with experimental autoimmune encephalomyelitis. Brain Res. 2012;1453:77–86.CrossRefPubMed
29.
Lourbopoulos A, Mourouzis I, Karapanayiotides T, Nousiopoulou E, Chatzigeorgiou S, Mavridis T, Kokkinakis I, Touloumi O, Irinopoulou T, Chouliaras K, et al. Changes in thyroid hormone receptors after permanent cerebral ischemia in male rats. J Mol Neurosci. 2014.
30.
Kim JE, Liu BP, Park JH, Strittmatter SM. Nogo-66 receptor prevents raphespinal and rubrospinal axon regeneration and limits functional recovery from spinal cord injury. Neuron. 2004;44:439–51.CrossRefPubMed
31.
McDonald CL, Steinbach K, Kern F, Schweigreiter R, Martin R, Bandtlow CE, Reindl M. Nogo receptor is involved in the adhesion of dendritic cells to myelin. J Neuroinflammation. 2011;8:113.CrossRefPubMedPubMedCentral
32.
Pool M, Niino M, Rambaldi I, Robson K, Bar-Or A, Fournier AE. Myelin regulates immune cell adhesion and motility. Exp Neurol. 2009;217:371–7.CrossRefPubMed
33.
Yan J, Zhou X, Guo JJ, Mao L, Wang YJ, Sun J, Sun LX, Zhang LY, Zhou XF, Liao H. Nogo-66 inhibits adhesion and migration of microglia via GTPase Rho pathway in vitro. J Neurochem. 2012;120:721–31.CrossRefPubMed
34.
Fang Y, Yan J, Li C, Zhou X, Yao L, Pang T, Yan M, Zhang L, Mao L, Liao H. The Nogo/Nogo receptor (NgR) signal is involved in neuroinflammation through the regulation of microglial inflammatory activation. J Biol Chem. 2015;290:28901–14.CrossRefPubMed
35.
Shin T, Kang B, Tanuma N, Matsumoto Y, Wie M, Ahn M, Kang J. Intrathecal administration of endothelin-1 receptor antagonist ameliorates autoimmune encephalomyelitis in Lewis rats. Neuroreport. 2001;12:1465–8.CrossRefPubMed
36.
Liu G, Ni J, Mao L, Yan M, Pang T, Liao H. Expression of Nogo receptor 1 in microglia during development and following traumatic brain injury. Brain Res. 2015.
37.
Kerschensteiner M, Bareyre FM, Buddeberg BS, Merkler D, Stadelmann C, Bruck W, Misgeld T, Schwab ME. Remodeling of axonal connections contributes to recovery in an animal model of multiple sclerosis. J Exp Med. 2004;200:1027–38.CrossRefPubMedPubMedCentral
38.
Trifunovski A, Josephson A, Ringman A, Brene S, Spenger C, Olson L. Neuronal activity-induced regulation of Lingo-1. Neuroreport. 2004;15:2397–400.CrossRefPubMed
39.
Mandemakers WJ, Barres BA. Axon regeneration: it’s getting crowded at the gates of TROY. Curr Biol. 2005;15:R302–5.CrossRefPubMed
40.
McDonald CL, Bandtlow C, Reindl M. Targeting the Nogo receptor complex in diseases of the central nervous system. Curr Med Chem. 2011;18:234–44.CrossRefPubMed
41.
Borrie SC, Baeumer BE, Bandtlow CE. The Nogo-66 receptor family in the intact and diseased CNS. Cell Tissue Res. 2012.
42.
Kraemer BR, Yoon SO, Carter BD. The biological functions and signaling mechanisms of the p75 neurotrophin receptor. Handb Exp Pharmacol. 2014;220:121–64.CrossRefPubMed
43.
Satoh J, Tabunoki H, Yamamura T, Arima K, Konno H. TROY and LINGO-1 expression in astrocytes and macrophages/microglia in multiple sclerosis lesions. Neuropathol Appl Neurobiol. 2007;33:99–107.CrossRefPubMed
44.
45.
46.
Jiang Z, Jiang JX, Zhang GX. Macrophages: a double-edged sword in experimental autoimmune encephalomyelitis. Immunol Lett. 2014;160:17–22.CrossRefPubMed
47.
Berard JL, Kerr BJ, Johnson HM, David S. Differential expression of SOCS1 in macrophages in relapsing-remitting and chronic EAE and its role in disease severity. Glia. 2010;58:1816–26.CrossRefPubMed
Metadata
Title
Nogo receptor complex expression dynamics in the inflammatory foci of central nervous system experimental autoimmune demyelination
Authors
Paschalis Theotokis
Olga Touloumi
Roza Lagoudaki
Evangelia Nousiopoulou
Evangelia Kesidou
Spyridon Siafis
Theodoros Tselios
Athanasios Lourbopoulos
Dimitrios Karacostas
Nikolaos Grigoriadis
Constantina Simeonidou
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/s12974-016-0730-4

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