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

Cytokine and chemokine alterations in tissue, CSF, and plasma in early presymptomatic phase of experimental allergic encephalomyelitis (EAE), in a rat model of multiple sclerosis

Authors: Nozha Borjini, Mercedes Fernández, Luciana Giardino, Laura Calzà

Published in: Journal of Neuroinflammation | Issue 1/2016

Login to get access

Abstract

Background

Experimental allergic encephalomyelitis (EAE) is the most commonly used experimental animal model for human multiple sclerosis (MS) that has been used so far to study the acute and remission-relapsing phases of the disease. Despite the vast literature on neuroinflammation onset and progression in EAE, important questions are still open regarding in particular the early asymptomatic phase between immunization and clinical onset.

Methods

In this study, we performed a time-course investigation of neuroinflammation and demyelination biomarkers in the spinal cord (SC), cerebrospinal fluid (CSF), and blood in EAE induced in dark agouti (DA) female rats compared to the controls and adjuvant-injected rats, using high-throughput technologies for gene expression and protein assays and focusing on the time-course between immunization, clinical onset (1, 5, 8 days post-immunization (DPI)), and progression (11 and 18 DPI). The expression profile of 84 genes related to T cell activation/signaling, adaptive immunity, cytokine/chemokine inflammation, demyelination, and cellular stress were analyzed in the tissue; 24 cytokines were measured in the CSF and plasma.

Results

The macrophage colony-stimulating factor (CSF1) was the first up-regulated protein as far as 1 DPI, not only in blood but also in CSF and SC. A treatment with GW2580, a selective CSF1R inhibitor, slowed the disease progression, significantly reduced the severity, and prevented the relapse phase. Moreover, both pro-inflammatory (IL-1β, TNF-α) and anti-inflammatory cytokines (IL-5, IL-10, VEGF) were up-regulated starting from 8 DPI. Myelin genes were down-regulated starting from 8 DPI, especially MAL, MBP, and PMP22 while an opposite expression profile was observed for inflammation-related genes, such as CXCL11 and CXCL10.

Conclusions

This early cytokine and chemokine regulation indicates that novel biomarkers and therapeutic options could be explored in the asymptomatic phase of EAE. Overall, our findings provide clear evidence that CSF1R signaling regulates inflammation in EAE, supporting therapeutic targeting of CSF1R in MS.
Literature
1.
2.
Hauser SL, Oksenberg JR. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron. 2006;52(1):61–76.CrossRefPubMed
3.
Hemmer B, Cepok S, Nessler S, Sommer N. Pathogenesis of multiple sclerosis: an update on immunology. Curr Opin Neurol. 2002;15(3):227–31.CrossRefPubMed
4.
Zigmond MJ, Coyle JT, Rowland LP. Neurobiology of brain disorders: biological basis of neurological and psychiatric disorders. London: Academic; 2015. p. 497–520.
5.
Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012;8(11):647–56.CrossRefPubMed
6.
Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545–58.CrossRefPubMed
7.
Aharoni R. New findings and old controversies in the research of multiple sclerosis and its model experimental autoimmune encephalomyelitis. Expert Rev Clin Immunol. 2013;9(5):423–40.CrossRefPubMed
8.
Guerreiro-Cacais AO, Laaksonen H, Flytzani S, N’diaye M, Olsson T, Jagodic M. Translational utility of experimental autoimmune encephalomyelitis: recent developments. J Inflamm Res. 2015;8:211–25.PubMedPubMedCentral
9.
Robinson AP, Harp CT, Noronha A, Miller SD. The experimental autoimmune encephalomyelitis (EAE) model of MS: utility for understanding disease pathophysiology and treatment. Handb Clin Neurol. 2014;122:173–89.CrossRefPubMedPubMedCentral
10.
Constantinescu CS, Farooqi N, O’Brien K, Gran B. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol. 2011;164(4):1079–106.CrossRefPubMedPubMedCentral
11.
t Hart BA, van Kooyk Y, Geurts JJ, Gran B. The primate autoimmune encephalomyelitis model; a bridge between mouse and man. Ann Clin Transl Neurol. 2015;2(5):581–93.CrossRef
12.
Ben-Nun A, et al. From classic to spontaneous and humanized models of multiple sclerosis: impact on understanding pathogenesis and drug development. J Autoimmun. 2014;54:33–50.CrossRefPubMed
13.
Piras G, Rattazzi L, McDermott A, Deacon R, D’Acquisto F. Emotional change-associated T cell mobilization at the early stage of a mouse model of multiple sclerosis. Front Immunol. 2013;4:400.
14.
Barkauskas DS, et al. Focal transient CNS vessel leak provides a tissue niche for sequential immune cell accumulation during the asymptomatic phase of EAE induction. Exp Neurol. 2015;266:74–85.CrossRefPubMedPubMedCentral
15.
Olechowski CJ, Truong JJ, Kerr BJ. Neuropathic pain behaviours in a chronic-relapsing model of experimental autoimmune encephalomyelitis (EAE). Pain. 2009;141(1–2):156–64.CrossRefPubMed
16.
Benson C, Paylor JW, Tenorio G, Winship I, Baker G, Kerr BJ. Voluntary wheel running delays disease onset and reduces pain hypersensitivity in early experimental autoimmune encephalomyelitis (EAE). Exp Neurol. 2015;271:279–90.CrossRefPubMed
17.
’t Hart BA, Gran B, Weissert R. EAE: imperfect but useful models of multiple sclerosis. Trends Mol Med. 2011;17(3):119–25.CrossRefPubMed
18.
Ringheim GE, et al. Teriflunomide attenuates immunopathological changes in the dark agouti rat model of experimental autoimmune encephalomyelitis. Front Neurol. 2013;4.
19.
Skundric DS. Experimental models of relapsing-remitting multiple sclerosis: current concepts and perspective. Curr Neurovasc Res. 2005;2(4):349–62.CrossRefPubMed
20.
Stadelmann C. Multiple sclerosis as a neurodegenerative disease: pathology, mechanisms and therapeutic implications. Curr Opin Neurol. 2011;24(3):224–9.CrossRefPubMed
21.
Bjartmar C, Wujek JR, Trapp BD. Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J Neurol Sci. 2003;206(2):165–71.CrossRefPubMed
22.
Calza L, Fernandez M, Giuliani A, Aloe L, Giardino L. Thyroid hormone activates oligodendrocyte precursors and increases a myelin-forming protein and NGF content in the spinal cord during experimental allergic encephalomyelitis. Proc Natl Acad Sci U S A. 2002;99(5):3258–63.CrossRefPubMedPubMedCentral
23.
Louhimies S, Louhimies S. Directive 86/609/EEC on the protection of animals used for experimental and other scientific purposes. Altern Lab Anim ATLA. 2002;30 Suppl 2:217–9.PubMed
24.
Gómez-Nicola D, Fransen NL, Suzzi S, Perry VH. Regulation of microglial proliferation during chronic neurodegeneration. J Neurosci Off J Soc Neurosci. 2013;33(6):2481–93.CrossRef
25.
Olmos-Alonso A, et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain. 2016;139(3):891–907.CrossRefPubMedPubMedCentral
26.
Leblond A-L, et al. Systemic and cardiac depletion of M2 macrophage through CSF-1R signaling inhibition alters cardiac function post myocardial infarction. PLoS One. 2015;10(9):e0137515.CrossRefPubMedPubMedCentral
27.
Conway JG, et al. Inhibition of colony-stimulating-factor-1 signaling in vivo with the orally bioavailable cFMS kinase inhibitor GW2580. Proc Natl Acad Sci U S A. 2005;102(44):16078–83.CrossRefPubMedPubMedCentral
28.
Hickey WF, Cohen JA, Burns JB. A quantitative immunohistochemical comparison of actively versus adoptively induced experimental allergic encephalomyelitis in the Lewis rat. Cell Immunol. 1987;109(2):272–81.CrossRefPubMed
29.
30.
31.
Blankesteijn M, Altara R. Inflammation in heart failure. 1st ed. New York: Academic; 2014.
32.
Kendziorski C, Irizarry RA, Chen K-S, Haag JD, Gould MN. On the utility of pooling biological samples in microarray experiments. Proc Natl Acad Sci U S A. 2005;102(12):4252–7.CrossRefPubMedPubMedCentral
33.
Kendziorski CM, Zhang Y, Lan H, Attie AD. The efficiency of pooling mRNA in microarray experiments. Biostat Oxf Engl. 2003;4(3):465–77.CrossRef
34.
Chabas D, et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science. 2001;294(5547):1731–5.CrossRefPubMed
35.
Yu W, Chen J, Xiong Y, Pixley FJ, Yeung Y-G, Stanley ER. Macrophage proliferation is regulated through CSF-1 receptor tyrosines 544, 559, and 807. J Biol Chem. 2012;287(17):13694–704.CrossRefPubMedPubMedCentral
36.
Calzà L, Giardino L, Pozza M, Micera A, Aloe L. Time-course changes of nerve growth factor, corticotropin-releasing hormone, and nitric oxide synthase isoforms and their possible role in the development of inflammatory response in experimental allergic encephalomyelitis. Proc Natl Acad Sci U S A. 1997;94(7):3368–73.CrossRefPubMedPubMedCentral
37.
Dell’Acqua ML, et al. Functional and molecular evidence of myelin- and neuroprotection by thyroid hormone administration in experimental allergic encephalomyelitis. Neuropathol Appl Neurobiol. 2012;38(5):454–70.CrossRefPubMed
38.
39.
Mildner A, et al. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer’s disease. J Neurosci Off J Soc Neurosci. 2011;31(31):11159–71.CrossRef
40.
41.
42.
Semple BD, Kossmann T, Morganti-Kossmann MC. Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2010;30(3):459–73.CrossRef
43.
Guo Y-Q, et al. Expression of CCL2 and CCR2 in the hippocampus and the interventional roles of propofol in rat cerebral ischemia/reperfusion. Exp Ther Med. 2014;8(2):657–61.PubMedPubMedCentral
44.
Kumar A, Stoica BA, Sabirzhanov B, Burns MP, Faden AI, Loane DJ. Traumatic brain injury in aged animals increases lesion size and chronically alters microglial/macrophage classical and alternative activation states. Neurobiol Aging. 2013;34(5):1397–411.CrossRefPubMed
45.
Morganti JM, Riparip L-K, Rosi S. Call off the Dog(ma): M1/M2 polarization is concurrent following traumatic brain injury. PLoS One. 2016;11(1):e0148001.CrossRefPubMedPubMedCentral
46.
Lee HK, et al. Daam2-PIP5K is a regulatory pathway for Wnt signaling and therapeutic target for remyelination in the CNS. Neuron. 2015;85(6):1227–43.CrossRefPubMedPubMedCentral
47.
Emery B. Regulation of oligodendrocyte differentiation and myelination. Science. 2010;330(6005):779–82.CrossRefPubMed
48.
49.
Serada S, et al. IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2008;105(26):9041–6.CrossRefPubMedPubMedCentral
50.
Eugster H-P, Frei K, Kopf M, Lassmann H, Fontana A. IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. Eur J Immunol. 1998;28(7):2178–87.CrossRefPubMed
51.
Pixley FJ, Stanley ER. CSF-1 regulation of the wandering macrophage: complexity in action. Trends Cell Biol. 2004;14(11):628–38.CrossRefPubMed
52.
53.
Clark SC, Kamen R. The human hematopoietic colony-stimulating factors. Science. 1987;236(4806):1229–37.CrossRefPubMed
54.
Roth P, Stanley ER. The biology of CSF-1 and its receptor. Curr Top Microbiol Immunol. 1992;181:141–67.PubMed
55.
Lin H, et al. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science. 2008;320(5877):807–11.CrossRefPubMed
56.
Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci. 2014;15(5):300–12.CrossRefPubMed
57.
Erblich B, Zhu L, Etgen AM, Dobrenis K, Pollard JW. Absence of colony stimulation factor-1 receptor results in loss of microglia, disrupted brain development and olfactory deficits. PLoS One. 2011;6(10):e26317.
58.
Nandi S, et al. The CSF-1 receptor ligands IL-34 and CSF-1 exhibit distinct developmental brain expression patterns and regulate neural progenitor cell maintenance and maturation. Dev Biol. 2012;367(2):100–13.CrossRefPubMedPubMedCentral
59.
Hao A-J, Dheen ST, Ling E-A. Expression of macrophage colony-stimulating factor and its receptor in microglia activation is linked to teratogen-induced neuronal damage. Neuroscience. 2002;112(4):889–900.CrossRefPubMed
60.
Waisman A, Ginhoux F, Greter M, Bruttger J. Homeostasis of microglia in the adult brain: review of novel microglia depletion systems. Trends Immunol. 2015;(10):625–36.
61.
Guan Z, et al. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat Neurosci. 2016;19(1):94–101.CrossRefPubMed
62.
Martínez-Muriana A, et al. CSF1R Blockade Slows the Progression of Amyotrophic Lateral Sclerosis by Reducing Microgliosis and Invasion of Macrophages into Peripheral Nerves. Sci Rep. 2016;13(6):25663. 
63.
Crespo O, et al. Tyrosine kinase inhibitors ameliorate autoimmune encephalomyelitis in a mouse model of multiple sclerosis. J Clin Immunol. 2011;31(6):1010–20.CrossRefPubMedPubMedCentral
64.
Irvine KM, Burns CJ, Wilks AF, Su S, Hume DA, Sweet MJ. A CSF-1 receptor kinase inhibitor targets effector functions and inhibits pro-inflammatory cytokine production from murine macrophage populations. FASEB J Off Publ Fed Am Soc Exp Biol. 2006;20(11):1921–3.
65.
66.
Adzemovic MV, Adzemovic MZ, Zeitelhofer M, Eriksson U, Olsson T, Nilsson I. Imatinib ameliorates neuroinflammation in a rat model of multiple sclerosis by enhancing blood-brain barrier integrity and by modulating the peripheral immune response. PLoS One. 2013;8(2):e56586.CrossRefPubMed
67.
Hume DA, MacDonald KPA. Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. Blood. 2012;119(8):1810–20.CrossRefPubMed
68.
69.
Rahat MA, Hemmerlein B, Iragavarapu-Charyulu V. The regulation of angiogenesis by tissue cell-macrophage interactions. Mediators of Inflammation; 2016. (eBook).
70.
Hambardzumyan D, Gutmann DH, Kettenmann H. The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci. 2016;19(1):20–7.CrossRefPubMed
Metadata
Title
Cytokine and chemokine alterations in tissue, CSF, and plasma in early presymptomatic phase of experimental allergic encephalomyelitis (EAE), in a rat model of multiple sclerosis
Authors
Nozha Borjini
Mercedes Fernández
Luciana Giardino
Laura Calzà
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/s12974-016-0757-6

Other articles of this Issue 1/2016

Journal of Neuroinflammation 1/2016 Go to the issue

Research

Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis

Research

Reciprocal signals between microglia and neurons regulate α-synuclein secretion by exophagy through a neuronal cJUN-N-terminal kinase-signaling axis

Research

Complex molecular and functional outcomes of single versus sequential cytokine stimulation of rat microglia

Research

Adult obese mice suffer from chronic secondary brain injury after mild TBI

Research

Neuroprotective effects of bee venom phospholipase A2 in the 3xTg AD mouse model of Alzheimer’s disease

Research

Fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling