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-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 γδ T cells are all sources of IL-1β. In addition, γδ 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.

Regional astrocyte IFN signaling restricts pathogenesis during neurotropic viral infection

“…This enhanced BBB permeability is associated with earlier detection of WNV in hindbrain regions of the CNS, suggesting that astrocyte IFNAR signaling prevents or delays infection at this site. Altered expression of cytokines such as IL-1β also probably influences other functions of the BBB, including local antigen presentation (21,45) and perivascular capture of infiltrating leukocytes (9,46), as reflected by the broad parenchymal localization of CD3 + lymphocytes in our study. Regional differences in astrocyte signaling may also differentially impact regional differences in other neurovascular cell types, including endothelial cells.…”

Caspase-1–Processed Cytokines IL-1β and IL-18 Promote IL-17 Production by γδ and CD4 T Cells That Mediate Autoimmunity

“…It has already been shown that IL-1 and IL-23 can promote IL-17 production by memory CD4 T cells and gd T cells (7,24,25). IL-23R is not expressed on naive CD4 T cells but is upregulated in response to IL-1, IL-6, IL-21, and IL-23 signaling (26,27). Conversely, IL-1R and IL-23R are constitutively expressed by gd T cells (7,27).…”

“…IL-23R is not expressed on naive CD4 T cells but is upregulated in response to IL-1, IL-6, IL-21, and IL-23 signaling (26,27). Conversely, IL-1R and IL-23R are constitutively expressed by gd T cells (7,27). In this study, we examine the expression of IL-18R on CD4 and gd T cells.…”

Chemokines and chemokine receptors in the pathogenesis of multiple sclerosis

“…Kao posledica toga, CXCR4+ mononuklearni leukociti iz perivaskularnog prostora prelaze u tkivo CNS, gde naknadno indukuju demijelinizaciju. Proinflamatorni citokin IL-1 stimuliše endotelnu translokaciju CXCL12 u toku neuroinflamacije (38). Visoki nivoi hemokina CXCL12 izmereni su u likvoru pacijenata sa MS (39), a ekspresija CXCL12 je lokalizovana u reaktivnim astrocitima plakova kod obolelih (34,38,40).…”