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IL-1R Signaling within the Central Nervous System Regulates CXCL12 Expression at the Blood-Brain Barrier and Disease Severity during Experimental Autoimmune Encephalomyelitis

Erin E. McCandless^*, Matthew Budde, Jason R. Lees, Denise Dorsey, Eric Lyng and Robyn S. Klein^*,,¶

^*Department of Pathology and Immunology, Department of Radiology, Department of Molecular Biology and Pharmacology, Department of Internal Medicine, and ^¶Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO 63110

Multiple sclerosis (MS) is an autoimmune disease of the CNS characterized by disruption of the blood-brain barrier (BBB). This breach in CNS immune privilege allows undeterred trafficking of myelin-specific lymphocytes into the CNS where they induce demyelination. Although the mechanism of BBB compromise is not known, the chemokine CXCL12 has been implicated as a molecular component of the BBB whose pattern of expression is specifically altered during MS and which correlates with disease severity. The inflammatory cytokine IL-1β has recently been shown to contribute not only to BBB permeability but also to the development of IL-17-driven autoimmune responses. Using experimental autoimmune encephalomyelitis, the rodent model of MS, we demonstrate that IL-1β mediates pathologic relocation of CXCL12 during the induction phase of the disease, before the development of BBB disruption. We also show that CD4, CD8, and, surprisingly T cells are all sources of IL-1β. In addition, T cells are also targets of this cytokine, contributing to IL-1β-mediated production of IL-17. Finally, we show that the level of CNS IL-1R determines the clinical severity of experimental autoimmune encephalomyelitis. These data suggest that T cell-derived IL-1β contributes to loss of immune privilege during CNS autoimmunity via pathologic alteration in the expression of CXCL12 at the BBB.

Address correspondence and reprint requests to Dr. Robyn S. Klein, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address: rklein{at}id.wustl.edu.