Immunity 2014 Feb 20;40(2):187-98. doi: 10.1016/j.immuni.2013.11.022.
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.
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.
The team at Ozgene has over two decades of experience creating customised knockout and knock-in mice for pivotal medical research globally. Over 300 scientific publications are based on research using Ozgene mice.