Publication in detail

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

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

Yoshida, Y; Yoshimi, R; Yoshii, H; Kim, D; Dey, A; Xiong, H; Munasinghe, J; Yazawa, I; O', MJ; Donovan, ; Maximova, OA; Sharma, S; Zhu, J; Wang, H; 3rd Morse, HC; Ozato, K

NICHD, NINDS, NIAID, National Institutes of Health, Bethesda, MD 20892, USA. Mount Sinai School of Medicine, New York, NY 10029, USA.

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.

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