title: IL-1R signaling within the central nervous system regulates CXCL12 expression at the blood-brain barrier and disease severity during experimental autoimmune encephalomyelitis.
abstract: 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-1beta 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-1beta 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 gammadelta T cells are all sources of IL-1beta. In addition, gammadelta T cells are also targets of this cytokine, contributing to IL-1beta-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-1beta contributes to loss of immune privilege during CNS autoimmunity via pathologic alteration in the expression of CXCL12 at the BBB.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Erin E
authors.initials: EE
authors.lastname: McCandless
authors.forename: Matthew
authors.initials: M
authors.lastname: Budde
authors.forename: Jason R
authors.initials: JR
authors.lastname: Lees
authors.forename: Denise
authors.initials: D
authors.lastname: Dorsey
authors.forename: Eric
authors.initials: E
authors.lastname: Lyng
authors.forename: Robyn S
authors.initials: RS
authors.lastname: Klein
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology*; D054377:Chemokine CXCL12 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013116:Spinal Cord / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D017472:Receptors, Interleukin-1