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,
* School of Molecular and Microbial Biosciences,
Department of Pathology and
Bosch Institute, University of Sydney, Australia; and
Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Autonomous University Barcelona, Spain
IL-6 is crucial for the induction of many murine models of autoimmunity including experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. To establish the role of site-specific production of IL-6 in autoimmunity, we examined myelin oligodendrocyte glycoprotein immunization-induced EAE in transgenic mice (GFAP-IL6) with IL-6 production restricted to the cerebellum. Myelin oligodendrocyte glycoprotein-immunized (Mi-) GFAP-IL6 mice developed severe ataxia but no physical signs of spinal cord involvement, which was in sharp contrast to Mi-wild type (WT) animals that developed classical EAE with ascending paralysis. Immune pathology and demyelination were nearly absent from the spinal cord, but significantly increased in the cerebellum of Mi-GFAP-IL6 mice. Tissue damage in the cerebellum in the Mi-GFAP-IL6 mice was accompanied by increased total numbers of infiltrating leukocytes and increased proportions of both neutrophils and B-cells. With the exception of IL-17 mRNA, which was elevated in both control immunized and Mi-GFAP-IL6 cerebellum, the level of other cytokine and chemokine mRNAs were comparable with Mi-WT cerebellum whereas significantly higher levels of IFN-
and TNF-
mRNA were found in Mi-WT spinal cord. Thus, site-specific production of IL-6 in the cerebellum redirects trafficking away from the normally preferred antigenic site the spinal cord and acts as a leukocyte "sink" that markedly enhances the inflammatory cell accumulation and disease. The mechanisms underlying this process likely include the induction of specific chemokines, activation of microglia, and activation and loss of integrity of the blood-brain barrier present in the cerebellum of the GFAP-IL6 mice before the induction of EAE.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a New South Wales Spinal Cord Injury and Other Neurological Conditions Project Grant and a start up grant from the University of Sydney (to I.L.C.); and by SAF2008–00435, FP6 Integrated Project Exgenesis (LSHM-CT-2004–005272), and RETICS (REEM, RD07/0060/0002) to J.H. D.G. was supported by an Australian Postgraduate Award. M.J.H. and M.M. were postdoctoral fellows of the Deutsche Forschungsgemeinschaft HO3298/1–1 and Mu17–07/3–1, respectively. M.M. was also supported by the fund "Innovative Medical Research" of the University of Münster Medical School, Germany. A.Q. and E.S. were predoctoral fellows of the Ministerio de Educación y Ciencia, BES-2003–2427 and AP2003–0534, respectively. R.F. was supported by a University of Sydney International Research Scholarship. R.R. was a predoctoral fellow of Generalitat de Catalunya 2006FI-01355.
2 A.Q. and M.M. contributed equally to this work.
3 Current address: Department of Biochemistry (A.Q.) and Department of Pharmacology (E.S.), University of Washington, Seattle, WA.
4 Current address: Department of Neurology, University of Bonn, Germany.
5 Current address: Department of Microbiology-Immunology, Northwestern University, Chicago, IL.
6 Current address: Department of Neuropathology, University of Marburg, Germany.
7 Address correspondence and reprint requests to Dr. Iain L. Campbell, School of Molecular and Microbial Biosciences G08, University of Sydney, New South Wales, 2006, Australia. E-mail address: icamp{at}usyd.edu.au
8 Abbreviations used in this paper: MS, multiple sclerosis; KO, knockout; EAE, experimental autoimmune encephalomyelitis; T reg, regulatory T cell; MOG, myelin oligodendrocyte glycoprotein; BBB, blood-brain barrier; WT, wild type; LFB, luxol fast blue; RPA, RNase protection assay; Ni, nonimmunized; Ci, BSA-CFA-immunized; Mi, MOG-CFA-immunized.
9 The online version of this article contains supplemental material.
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