CCAAT/enhancer binding protein-delta expression by dendritic cells regulates CNS autoimmune inflammatory disease.

摘要

CCAAT enhancer binding protein-delta (C/EBPdelta) is a transcription factor that regulates inflammatory processes mediating bystander neuronal injury and CNS autoimmune inflammatory disease. The mechanism of the involvement of C/EBPdelta in these processes remains to be determined. Here, we examined the cellular source(s) and mechanisms by which C/EBPdelta may be involved in an animal model of multiple sclerosis. Mice deficient in C/EBPdelta expression exhibited less severe clinical disease than wild-type littermates in response to induction of experimental autoimmune encephalomyelitis (EAE) by vaccination with a myelin oligodendrocyte glycoprotein (MOG) fragment. This reduction in EAE severity was associated with a significant alteration in the complement of major CNS T-helper (Th) cell subtypes throughout disease, manifest as reduced ratios of Th17 cells to regulatory T-cells (Tregs). Studies in bone marrow chimeric mice indicated that C/EBPdelta expression by peripherally derived immune cells mediates C/EBPdelta involvement in EAE. Follow up in vitro and in vivo examination of dendritic cell (DC) mediated Th-cell development suggests that C/EBPdelta suppresses DC expression of interleukin-10 (IL-10), favoring Th17 over Treg development. In vitro and in vivo blockade of IL-10 signaling attenuated the effect of reduced C/EBPdelta expression by DCs on Th17:Treg ratios. These findings identify C/EBPdelta as an important DC transcription factor in CNS autoimmune inflammatory disease by virtue of its capacity to alter the Th17:Treg balance in an IL-10 dependent fashion.