Abstract
Multiple sclerosis is an autoimmune disease of the central nervous system characterized by neuroinflammation and demyelination. Although considered a T cell-mediated disease, multiple sclerosis involves the activation of both adaptive and innate immune cells, as well as resident cells of the central nervous system, which synergize in inducing inflammation and thereby demyelination. Differentiation, survival, and inflammatory functions of innate immune cells and of astrocytes of the central nervous system are regulated by tyrosine kinases. Here, we show that imatinib, sorafenib, and GW2580—small molecule tyrosine kinase inhibitors—can each prevent the development of disease and treat established disease in a mouse model of multiple sclerosis. In vitro, imatinib and sorafenib inhibited astrocyte proliferation mediated by the tyrosine kinase platelet-derived growth factor receptor (PDGFR), whereas GW2580 and sorafenib inhibited macrophage tumor necrosis factor (TNF) production mediated by the tyrosine kinases c-Fms and PDGFR, respectively. In vivo, amelioration of disease by GW2580 was associated with a reduction in the proportion of macrophages and T cells in the CNS infiltrate, as well as a reduction in the levels of circulating TNF. Our findings suggest that GW2580 and the FDA-approved drugs imatinib and sorafenib have potential as novel therapeutics for the treatment of autoimmune demyelinating disease.
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Abbreviations
- MS:
-
Multiple sclerosis
- EAE:
-
Experimental autoimmune encephalomyelitis
- MOG:
-
Myelin oligodendrocyte glycoprotein
- TKI:
-
Tyrosine kinase inhibitor
- PDGFR:
-
Platelet-derived growth factor receptor
- PDGF:
-
Platelet-derived growth factor
- c-Fms:
-
Colony-stimulating factor 1 receptor
- MCSF:
-
Macrophage colony-stimulating factor
- CFA:
-
Complete Freund’s adjuvant
- TNF:
-
Tumor necrosis factor
- IL:
-
Interleukin
- CNS:
-
Central nervous system
- FCS:
-
Fetal calf serum
- NEAA:
-
Non-essential amino acids
- LFB:
-
Luxol fast blue
- HBSS:
-
Hank’s buffered salt solution
References
Steinman L. Multiple sclerosis: a two-stage disease. Nat Immunol. 2001;2:762–4.
Hedegaard CJ, Krakauer M, Bendtzen K, Lund H, Sellebjerg F, Nielsen CH. T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis. Immunology. 2008;125:161–9.
Oh S, Cudrici C, Ito T, Rus H. B-cells and humoral immunity in multiple sclerosis. Implications for therapy. Immunol Res. 2007;40(3):224–34.
Storch MK, Piddlesden S, Haltia M, Iivanainen M, Morgan P, Lassmann H. Multiple sclerosis: in situ evidence for antibody- and complement-mediated demyelination. Ann Neurol. 1998;43:465–71.
Benveniste E. Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J Mol Med. 1997;75(3):165–73.
Huitinga I, Ruuls SR, Jung S, Van Rooijen N, Hartung HP, Dijkstra CD. Macrophages in T cell line-mediated, demyelinating, and chronic relapsing experimental autoimmune encephalomyelitis in Lewis rats. Clin Exp Immunol. 1995;100:344–51.
Sayed BA, Christy AL, Walker ME, Brown MA. Meningeal mast cells affect early T cell central nervous system infiltration and blood-brain barrier integrity through TNF: a role for neutrophil recruitment? J Immunol. 2010;184(12):6891–900.
Vercellino M, Merola A, Piacentino C, Votta B, Capello E, Mancardi GL, et al. Altered glutamate reuptake in relapsing-remitting and secondary progressive multiple sclerosis cortex: correlation with microglia infiltration, demyelination, and neuronal and synaptic damage. J Neuropathol Exp Neurol. 2007;66:732–9.
Werner P, Pitt D, Raine CS. Multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage. Ann Neurol. 2001;50:169–80.
Steinman L, Zamvil SS. Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis. Trends Immunol. 2005;26:565–71.
Healy BC, Engler D, Gholipour T, Weiner H, Bakshi R, Chitnis T. Accounting for disease modifying therapy in models of clinical progression in multiple sclerosis. J Neurol Sci. 2011;303(1–2):109–13.
Liblau R. Glatiramer acetate for the treatment of multiple sclerosis: evidence for a dual anti-inflammatory and neuroprotective role. J Neurol Sci. 2009;287:S17–23.
Vos CM, van Haastert ES, de Groot CJ, van der Valk P, de Vries HE. Matrix metalloproteinase-12 is expressed in phagocytotic macrophages in active multiple sclerosis lesions. J Neuroimmunol. 2003;138:106–14.
Bruck W, Friede RL. L-fucosidase treatment blocks myelin phagocytosis by macrophages in vitro. J Neuroimmunol. 1990;27:217–27.
Zhang X, Haaf M, Todorich B, Grosstephan E, Schieremberg H, Surguladze N, et al. Cytokine toxicity to oligodendrocyte precursors is mediated by iron. Glia. 2005;52:199–208.
Kassiotis G, Kollias G. TNF and receptors in organ-specific autoimmune disease: multi-layered functioning mirrored in animal models. J Clin Invest. 2001;107:1507–8.
Kollias G, Douni E, Kassiotis G, Kontoyiannis D. On the role of tumor necrosis factor and receptors in models of multiorgan failure, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. Immunol Rev. 1999;169:175–94.
Bhasin M, Wu M, Tsirka SE. Modulation of microglial/macrophage activation by macrophage inhibitory factor (TKP) or tuftsin (TKPR) attenuates the disease course of experimental autoimmune encephalomyelitis. BMC Immunol. 2007;8:10.
Martiney JA, Rajan AJ, Charles PC, Cerami A, Ulrich PC, Macphail S, et al. Prevention and treatment of experimental autoimmune encephalomyelitis by CNI-1493, a macrophage-deactivating agent. J Immunol. 1998;160:5588–95.
Brosnan CF, Bornstein MB, Bloom BR. The effects of macrophage depletion on the clinical and pathologic expression of experimental allergic encephalomyelitis. J Immunol. 1981;126:614–20.
Huitinga I, van Rooijen N, de Groot CJ, Uitdehaag BM, Dijkstra CD. Suppression of experimental allergic encephalomyelitis in Lewis rats after elimination of macrophages. J Exp Med. 1990;172:1025–33.
Tran EH, Hoekstra K, van Rooijen N, Dijkstra CD, Owens T. Immune invasion of the central nervous system parenchyma and experimental allergic encephalomyelitis, but not leukocyte extravasation from blood, are prevented in macrophage-depleted mice. J Immunol. 1998;161:3767–75.
Cecchini MG, Dominguez MG, Mocci S, Wetterwald A, Felix R, Fleisch H, et al. Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse. Development. 1994;120(6):1357–72.
MacDonald KP, Palmer JS, Cronau S, Seppanen E, Olver S, Raffelt NC, et al. An antibody against the colony-stimulating factor 1 receptor depletes the resident subset of monocytes and tissue- and tumor-associated macrophages but does not inhibit inflammation. Blood. 2010;116:3955–63.
Sasaki A, Yokoo H, Naito M, Kaizu C, Shultz LD, Nakazato Y. Effects of macrophage-colony-stimulating factor deficiency on the maturation of microglia and brain macrophages and on their expression of scavenger receptor. Neuropathology. 2000;20:134–42.
Wiktor-Jedrzejczak WW, Ahmed A, Szczylik C, Skelly RR. Hematological characterization of congenital osteopetrosis in op/op mouse. Possible mechanism for abnormal macrophage differentiation. J Exp Med. 1982;156:1516–27.
Pradervand S, Maurya M, Subramaniam S. Identification of signaling components required for the prediction of cytokine release in RAW 264.7 macrophages. Genome Biol. 2006;7(2):R11.
Campbell IK, Rich MJ, Bischof RJ, Hamilton JA. The colony-stimulating factors and collagen-induced arthritis: exacerbation of disease by M-CSF and G-CSF and requirement for endogenous M-CSF. J Leukoc Biol. 2000;68:144–50.
Gallo P, Pagni S, Giometto B, Piccinno MG, Bozza F, Argentiero V, et al. Macrophage-colony stimulating factor (M-CSF) in the cerebrospinal fluid. J Neuroimmunol. 1990;29:105–12.
D'Alfonso S, Nistico L, Zavattari P, Marrosu MG, Murru R, Lai M, et al. Linkage analysis of multiple sclerosis with candidate region markers in Sardinian and Continental Italian families. Eur J Hum Genet. 1999;7:377–85.
Campbell IL, Eddleston M, Kemper P, Oldstone MB, Hobbs MV. Activation of cerebral cytokine gene expression and its correlation with onset of reactive astrocyte and acute-phase response gene expression in scrapie. J Virol. 1994;68:2383–7.
Ransom B, Behar T, Nedergaard M. New roles for astrocytes (stars at last). Trends Neurosci. 2003;26:520–2.
Williams A, Piaton G, Lubetzki C. Astrocytes—friends or foes in multiple sclerosis? Glia. 2007;55:1300–12.
Bannerman P, Hahn A, Soulika A, Gallo V, Pleasure D. Astrogliosis in EAE spinal cord: derivation from radial glia, and relationships to oligodendroglia. Glia. 2006;55(1):57–64.
Luo J, Miller MW. Platelet-derived growth factor-mediated signal transduction underlying astrocyte proliferation: site of ethanol action. J Neurosci. 1999;19:10014–25.
Koehler NK, Roebbert M, Dehghani K, Ballmaier M, Claus P, von Hoersten S, et al. Up-regulation of platelet-derived growth factor by peripheral-blood leukocytes during experimental allergic encephalomyelitis. J Neurosci Res. 2008;86:392–402.
Paniagua RT. Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis. J Clin Invest. 2006;116(10):2633–42.
Louvet C, Szot G, Lang J, Lee M, Martinier N, Bollag G, et al. Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice. Proc Natl Acad Sci U S A. 2008;105(48):18895–900.
Stromnes IM, Goverman JM. Active induction of experimental allergic encephalomyelitis. Nat Protoc. 2006;1:1810–9.
Paniagua RT, Chang A, Mariano MM, Stein EA, Wang Q, Lindstrom TM, et al. c-Fms-mediated differentiation and priming of monocyte lineage cells play a central role in autoimmune arthritis. Arthritis Res Ther. 2010;12(1):R32.
Druker B, Talpaz M, Resta D, Peng B, Buchdunger E, Ford J, et al. Sawyers C (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031–7.
Wolff NC, Randle DE, Egorin MJ, Minna JD, Ilaria Jr RL. Imatinib mesylate efficiently achieves therapeutic intratumor concentrations in vivo but has limited activity in a xenograft model of small cell lung cancer. Clin Cancer Res. 2004;10:3528–34.
Huynh H, Lee JW, Chow PK, Ngo VC, Lew GB, Lam IW, et al. Sorafenib induces growth suppression in mouse models of gastrointestinal stromal tumor. Mol Cancer Ther. 2009;8:152–9.
Chung EJ, Yoo S, Lim HJ, Byeon SH, Lee JH, Koh HJ. Inhibition of choroidal neovascularisation in mice by systemic administration of the multikinase inhibitor, sorafenib. Br J Ophthalmol. 2009;93:958–63.
Strumberg D, Voliotis D, Moeller JG, Hilger RA, Richly H, Kredtke S, et al. Results of phase I pharmacokinetic and pharmacodynamic studies of the Raf kinase inhibitor BAY 43–9006 in patients with solid tumors. Int J Clin Pharmacol Ther. 2002;40:580–1.
Conway JG, McDonald B, Parham J, Keith B, Rusnak DW, Shaw E, et al. Inhibition of colony-stimulating-factor-1 signaling in vivo with the orally bioavailable cFMS kinase inhibitor GW2580. Proc Natl Acad Sci USA. 2005;102(44):16078–83.
Katz-Levy Y, Neville KL, Girvin AM, Vanderlugt CL, Pope JG, Tan LJ, et al. Endogenous presentation of self myelin epitopes by CNS-resident APCs in Theiler's virus-infected mice. J Clin Invest. 1999;104:599–610.
Awada A, Hendlisz A, Gil T, Bartholomeus S, Mano M, De Valeriola D, et al. Phase I safety and pharmacokinetics of BAY 43–9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br J Cancer. 2005;92(10):1855–61.
Wilhelm S, Chien DS. BAY 43–9006: preclinical data. Curr Pharm Des. 2002;8:2255–7.
Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7(10):3129–40.
Tong FK, Chow S, HD. Pharmacodynamic monitoring of BAY 43-9006 (Sorafenib) in phase I clinical trials involving solid tumor and AML/MDS patients, using flow cytometry to monitor activation of the ERK pathway in peripheral blood cells. Cytometry B Clin Cytom. 2006;70(3):107–14.
Conway JG, McDonald B, Parham J, Keith B, Rusnak DW, Shaw E, et al. Inhibition of colony-stimulating-factor-1 signaling in vivo with the orally bioavailable cFMS kinase inhibitor GW2580. Proc Natl Acad Sci USA. 2005;102:16078–83.
Valcamonico F, Ferrari V, Amoroso V, Rangoni G, Simoncini E, Marpicati P, et al. Long-lasting successful cerebral response with sorafenib in advanced renal cell carcinoma. J Neurooncol. 2009;9(1):47–50.
Czyzewski K, Styczynski J. Imatinib is a substrate for various multidrug resistance proteins. Neoplasma. 2009;56:202–7.
Tonra JR, Reiseter BS, Kolbeck R, Nagashima K, Robertson R, Keyt B, et al. Comparison of the timing of acute blood-brain barrier breakdown to rabbit immunoglobulin G in the cerebellum and spinal cord of mice with experimental autoimmune encephalomyelitis. J Comp Neurol. 2001;430:131–44.
Uemura Y, Ohno H, Ohzeki Y, Takanashi H, Murooka H, Kubo K, et al. The selective M-CSF receptor tyrosine kinase inhibitor Ki20227 suppresses experimental autoimmune encephalomyelitis. J Neuroimmunol. 2008;195:73–80.
Lock C, Oksenberg J, Steinman L. The role of TNFalpha and lymphotoxin in demyelinating disease. Ann Rheum Dis. 1999;58 Suppl 1:I121–8.
Sharief MK, Hentges R. Association between tumor necrosis factor-alpha and disease progression in patients with multiple sclerosis. N Engl J Med. 1991;325:467–72.
Sicotte NL, Voshkul RR. Onset of multiple sclerosis associated with anti-TNF therapy. Neurology. 2001;57(10):1885–8.
Robinson WH, Genovese MC, Moreland LW. Demyelinating and neurologic events reported in association with tumor necrosis factor alpha antagonism: by what mechanisms could tumor necrosis factor alpha antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis? Arthritis Rheum. 2001;44:1977–83.
El Chartouni C, Benner C, Eigner M, Lichtinger M, Rehli M. Transcriptional effects of colony-stimulating factor-1 in mouse macrophages. Immunobiology. 2010;215(6):466–74.
Dalton D, Wittmer S. Nitric-oxide-dependent and independent mechanisms of protection from CNS inflammation during Th1-mediated autoimmunity: evidence from EAE in iNOS KO mice. J Neuroimmunol. 2005;160(1–2):110–21.
Rovida E, Baccarini M, Olivotto M, Dello Sbarba P. Opposite effects of different doses of MCSF on ERK phosphorylation and cell proliferation in macrophages. Oncogene. 2002;21:3670–6.
Karpiak VC, Bridges RJ, Eyer CL. Organotins disrupt components of glutamate homeostasis in rat astrocyte cultures. J Toxicol Environ Health A. 2001;63:273–87.
Conway J, Pink H, Bergquist M, Han B, Depee S, Tadepalli S, et al. Effects of the cFMS kinase inhibitor 5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580) in normal and arthritic rats. J Pharmacol Exp Ther. 2008;326(1):41–50.
Valdo P, Stegagno C, Mazzucco S, Zuliani E, Zanusso G, Moretto G, et al. Enhanced expression of NGF receptors in multiple sclerosis lesions. J Neuropathol Exp Neurol. 2002;61:91–8.
Acknowledgments
We thank Ben Barres’ group, in particular Maria Fabian, for kindly providing the rat primary astrocytes. We also thank Jane Eaton for providing guidance through the histopathology tissue-staining process. This work was supported by National Institutes of Health (NIH) National Heart Lung and Blood Institute contract N01-HV-00242, NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases R01 AR-054822, and Veterans Affairs Health Care System funding awarded to WHR. OC received funding from the NIH training grant 5 T32 AI07290 for Molecular and Cellular Immunobiology.
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Crespo, O., Kang, S.C., Daneman, R. et al. Tyrosine Kinase Inhibitors Ameliorate Autoimmune Encephalomyelitis in a Mouse Model of Multiple Sclerosis. J Clin Immunol 31, 1010–1020 (2011). https://doi.org/10.1007/s10875-011-9579-6
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DOI: https://doi.org/10.1007/s10875-011-9579-6