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

• Published in: The Journal of neuroscience 2011-11, Vol.31 (48), p.17612-17621
• Main Authors: Tsai, Vicky W W, Mohammad, Mohammad G, Tolhurst, Ornella, Breit, Samuel N, Sawchenko, Paul E, Brown, David A
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes - immunology; Astrocytes - metabolism; CCAAT-Enhancer-Binding Protein-delta - genetics; CCAAT-Enhancer-Binding Protein-delta - metabolism; Dendritic Cells - immunology; Dendritic Cells - metabolism; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Interleukin-10 - metabolism; Mice; Mice, Knockout; Myelin-Associated Glycoprotein - immunology; Myelin-Associated Glycoprotein - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Th17 Cells - immunology; Th17 Cells - metabolism; Up-Regulation
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3449-11.2011

CCAAT enhancer binding protein-delta (C/EBPδ) is a transcription factor that regulates inflammatory processes mediating bystander neuronal injury and CNS autoimmune inflammatory disease. The mechanism of the involvement of C/EBPδ in these processes remains to be determined. Here, we examined the cellular source(s) and mechanisms by which C/EBPδ may be involved in an animal model of multiple sclerosis. Mice deficient in C/EBPδ 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/EBPδ expression by peripherally derived immune cells mediates C/EBPδ involvement in EAE. Follow up in vitro and in vivo examination of dendritic cell (DC) mediated Th-cell development suggests that C/EBPδ 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/EBPδ expression by DCs on Th17:Treg ratios. These findings identify C/EBPδ 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.