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* Corinne Goldsmith Dickinson Center for Multiple Sclerosis,
Department of Neurology, and
Department of Microbiology and Immunology, Mount Sinai School of Medicine, New York, NY 10029
Current therapies for the autoimmune demyelinating disease multiple sclerosis (MS) target inflammation, but do not directly address neuroprotection or lesion repair. Cytokines of the gp130 family regulate survival and differentiation of both neural and immune cells, and we recently identified expression of the family member IL-11 in active MS plaques. In this study, we show that IL-11 regulates the clinical course and neuropathology of experimental autoimmune encephalomyelitis, a demyelinating model that mimics many of the clinical and pathologic features of MS. Importantly, the effects of IL-11 are achieved via a combination of immunoregulation and direct neuroprotection. IL-11R-
-null (IL-11R–/–) mice displayed a significant increase in clinical severity and neuropathology of experimental autoimmune encephalomyelitis compared with wild-type littermates. Inflammation, demyelination, and oligodendrocyte and neuronal loss were all exacerbated in IL-11Ra–/– animals. Conversely, wild-type mice treated with IL-11 displayed milder clinical signs and neuropathology than vehicle-treated controls. In cocultures of murine myelin oligodendrocyte glycoprotein35–55-specific CD4+ T lymphocytes and CD11c+ APCs, IL-11 treatment resulted in a significant decrease in T cell-derived effector cytokine production. This effect was generated via modulation of CD11c+ APC-mediated lymphocyte activation, and was associated with a decrease in the size of the CD11c+ cell population. Conversely, IL-11 strongly reduced apoptosis and potentiated mitosis in primary cultures of mouse oligodendrocyte progenitors. Collectively, these data reveal that IL-11 regulates inflammatory demyelination via a unique combination of immunoregulation and neuroprotection. IL-11 signaling may represent a therapeutic avenue to restrict CNS inflammation and potentiate oligodendrocyte survival in autoimmune demyelinating disease.
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 U.S. Public Health Service Grants R01 NS056074 and R01 NS046620 (to G.R.J.), R21 AI077007 (to T.M.M. and C.B.L.), R01 AI041111 (to T.M.M. and C.B.L.), T32-GM-008553-13 (to B.T.G.), National Multiple Sclerosis Society Fellowship FG-1739 (to Y.Z.), Research Grant RG-3874 (to G.R.J.), and the Jayne and Harvey Beker Foundation (to G.R.J.). The Mount Sinai School of Medicine/Microscopy Shared Resource Facility is supported, in part, by funding from National Institutes of Health/National Cancer Institute Shared Resources Grant R24 CA095823.
2 Address correspondence and reprint requests to Dr. Gareth R. John, Department of Neurology, Annenberg 14-86, Box 11-37, Mount Sinai School of Medicine, New York, NY 10029. E-mail address: gareth.john{at}mssm.edu
3 Abbreviations used in this paper: MS, multiple sclerosis; BBB, blood-brain barrier; CNTF, ciliary neurotrophic factor; DAPI, 4',6-diamidino-2-phenylindole; EAE, experimental autoimmune encephalomyelitis; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; OPC, oligodendrocyte progenitor cell; CNPase, 2',3'-cyclic nucleotide phosphodiesterase; MHCII, MHC class II.
4 The online version of this article contains supplemental material.
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