The transcription factor IRF8 activates integrin-mediated TGF-β signaling and promotes neuroinflammation.
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.
Program in Genomics of Differentiation, NICHD, National Institutes of Health, Bethesda, MD 20892, USA.
Yuko
Y
Yoshida
Program in Genomics of Differentiation, NICHD, National Institutes of Health, Bethesda, MD 20892, USA.
Ryusuke
R
Yoshimi
Program in Genomics of Differentiation, NICHD, National Institutes of Health, Bethesda, MD 20892, USA.
Hiroaki
H
Yoshii
Program in Genomics of Differentiation, NICHD, National Institutes of Health, Bethesda, MD 20892, USA.
Daniel
D
Kim
Program in Genomics of Differentiation, NICHD, National Institutes of Health, Bethesda, MD 20892, USA.
Anup
A
Dey
Immunology Institute, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Huabao
H
Xiong
Laboratory of Functional and Molecular Imaging, NINDS, National Institutes of Health, Bethesda, MD 20892, USA.
Jeeva
J
Munasinghe
Laboratory of Neural Control, NINDS, National Institutes of Health, Bethesda, MD 20892, USA.
Itaru
I
Yazawa
Laboratory of Neural Control, NINDS, National Institutes of Health, Bethesda, MD 20892, USA.
Michael J
MJ
O'Donovan
Laboratory of Infectious Diseases, NIAID, National Institutes of Health, Bethesda, MD 20892, USA.
Olga A
OA
Maximova
Laboratory of Immunology, NIAID, National Institutes of Health, Bethesda, MD 20892, USA.
Suveena
S
Sharma
Laboratory of Immunology, NIAID, National Institutes of Health, Bethesda, MD 20892, USA.
Jinfang
J
Zhu
Laboratory of Immunogenetics, NIAID, National Institutes of Health, Rockville, MD 20892, USA.
Hongsheng
H
Wang
Laboratory of Immunogenetics, NIAID, National Institutes of Health, Rockville, MD 20892, USA.
Herbert C
HC
Morse
Program in Genomics of Differentiation, NICHD, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: ozatok@nih.gov.
Keiko
K
Ozato
D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000503:physiopathology; D005434:Flow Cytometry; D007249:Inflammation / Q000503:physiopathology*; D016023:Integrins / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000099185:Interferon Regulatory Factor-8
D016023:Integrins; D050835:Interferon Regulatory Factors; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D000099185:Interferon Regulatory Factor-8