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Immunity. 2014 Feb 20;40(2):187-98. doi: 10.1016/j.immuni.2013.11.022. Epub 2014 Jan 30.

The transcription factor IRF8 activates integrin-mediated TGF-β signaling and promotes neuroinflammation.

Author information

1
Program in Genomics of Differentiation, NICHD, National Institutes of Health, Bethesda, MD 20892, USA.
2
Immunology Institute, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
3
Laboratory of Functional and Molecular Imaging, NINDS, National Institutes of Health, Bethesda, MD 20892, USA.
4
Laboratory of Neural Control, NINDS, National Institutes of Health, Bethesda, MD 20892, USA.
5
Laboratory of Infectious Diseases, NIAID, National Institutes of Health, Bethesda, MD 20892, USA.
6
Laboratory of Immunology, NIAID, National Institutes of Health, Bethesda, MD 20892, USA.
7
Laboratory of Immunogenetics, NIAID, National Institutes of Health, Rockville, MD 20892, USA.
8
Program in Genomics of Differentiation, NICHD, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: ozatok@nih.gov.

Abstract

Recent epidemiological studies have identified interferon regulatory factor 8 (IRF8) as a susceptibility factor for multiple sclerosis (MS). However, how IRF8 influences the neuroinflammatory disease has remained unknown. By studying the role of IRF8 in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, we found that Irf8(-/-) mice are resistant to EAE. Furthermore, expression of IRF8 in antigen-presenting cells (APCs, such as macrophages, dendritic cells, and microglia), but not in T cells, facilitated disease onset and progression through multiple pathways. IRF8 enhanced αvβ8 integrin expression in APCs and activated TGF-β signaling leading to T helper 17 (Th17) cell differentiation. IRF8 induced a cytokine milieu that favored growth and maintenance of Th1 and Th17 cells, by stimulating interleukin-12 (IL-12) and IL-23 production, but inhibiting IL-27 during EAE. Finally, IRF8 activated microglia and exacerbated neuroinflammation. Together, this work provides mechanistic bases by which IRF8 contributes to the pathogenesis of MS.

PMID:
24485804
PMCID:
PMC4105266
DOI:
10.1016/j.immuni.2013.11.022
[Indexed for MEDLINE]
Free PMC Article
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