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B Improves Functional Outcome in Experimental Autoimmune Encephalomyelitis by Suppressing Chronic Central Nervous System Inflammation1
,
,#
* The Miami Project to Cure Paralysis,
Bascom Palmer Eye Institute,
Department of Cell Biology and Anatomy,
Department of Molecular and Cellular Pharmacology,
¶ Neuroscience Program, and
|| Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136;
# Vavilov Institute of General Genetics, Russian Academy of Science, Moscow, Russian Federation; and
** Departments of Microbiology and Neurology, University of Alabama, Birmingham, AL 35294
In the CNS, the transcription factor NF-
B is a key regulator of inflammation and secondary injury processes. Following trauma or disease, the expression of NF-B-dependent genes is activated, leading to both protective and detrimental effects. In this study, we show that transgenic inactivation of astroglial NF-B (glial fibrillary acidic protein-IB
-dominant-negative mice) resulted in reduced disease severity and improved functional recovery following experimental autoimmune encephalomyelitis. At the chronic stage of the disease, transgenic mice exhibited an overall higher presence of leukocytes in spinal cord and brain, and a markedly higher percentage of CD8+CD122+ T regulatory cells compared with wild type, which correlated with the timing of clinical recovery. We also observed that expression of proinflammatory genes in both spinal cord and cerebellum was delayed and reduced, whereas the loss of neuronal-specific molecules essential for synaptic transmission was limited compared with wild-type mice. Furthermore, death of retinal ganglion cells in affected retinas was almost abolished, suggesting the activation of neuroprotective mechanisms. Our data indicate that inhibiting NF-B in astrocytes results in neuroprotective effects following experimental autoimmune encephalomyelitis, directly implicating astrocytes in the pathophysiology of this 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 National Institutes of Health Grants NS051709 (to J.R.B.), NS46032 (to S.R.B.), and EY017991 (to V.I.S.), and The Miami Project To Cure Paralysis.
2 Address correspondence and reprint requests to Dr. Roberta Brambilla or Dr. John R. Bethea, The Miami Project To Cure Paralysis, University of Miami Miller School of Medicine, 1095 Northwest 14th Terrace, Miami, FL 33136; E-mail addresses: r.brambilla{at}miami.edu or JBethea{at}miami.edu
3 Abbreviations used in this paper: MS, multiple sclerosis; BBB, blood-brain barrier; dn, dominant negative; dpi, days postinduction; EAE, experimental autoimmune encephalomyelitis; FDR, false discovery rate; GFAP, glial fibrillary acidic protein; Itg, integrin; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; RGC, retinal ganglion cell; Treg, T regulatory cell; WT, wild type; CDI, cumulative disease index.
4 The online version of this article contains supplementary material.
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  R. R. Voskuhl, R. S. Peterson, B. Song, Y. Ao, L. B. J. Morales, S. Tiwari-Woodruff, and M. V. Sofroniew Reactive Astrocytes Form Scar-Like Perivascular Barriers to Leukocytes during Adaptive Immune Inflammation of the CNS J. Neurosci., September 16, 2009; 29(37): 11511 - 11522. [Abstract] [Full Text] [PDF]
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