IFNbeta inhibits DC migration in vitro and in vivo (92.2)

Abstract

Abstract Interferon β (IFN β) is a widely approved therapeutic option for the treatment of multiple sclerosis (MS)/experimental autoimmune encephalomyelitis (EAE). However, the molecular mechanisms underlying the effects of IFNβ in MS/EAE are still not fully understood. In EAE, the major players are encephalitogenic CD4+ T cells and perivascular myeloid dendritic cells (DC). Therefore, migration of both peripheral T cells and DC into the CNS is essential for development of EAE/MS. Migration of DC from the inflammatory site to draining lymph nodes for antigen presentation and activation of naïve T cells, and to the CNS during chronic neuroinflammation requires CCR7 and MMP-9 expression. In this study, we report for the first time that IFNβ inhibits CCR7 expression and MMP-9 production in DC matured with a cytokine cocktail (TNFα+IL-1+IL-6+PGE2). In addition, DC matured in the presence of IFNβ exhibit a lower migratory capacity compared to mature DC. STAT-1 signaling is essential for IFNβ-mediated inhibition of CCR7 and MMP-9 expression, and subsequent DC migration. Our in vivo data also show that mice treated with IFNβ have a lower number of DC migrating to the draining lymph nodes following exposure to FITC as compared to controls. In conclusion, our results provide an addition mechanism for the beneficial effect of IFNβ in MS/EAE through the inhibition of mature DC migration. This work is support by NIH 2RO1AI052306