The Transcription Factor IRF8 Activates Integrin-Mediated TGF-? Signaling and Promotes Neuroinflammation

• Published in: Immunity (Cambridge, Mass.) Mass.), 2014-02, Vol.40 (2), p.187
• Main Authors: Yoshida, Yuko, Yoshimi, Ryusuke, Yoshii, Hiroaki, Kim, Daniel, Dey, Anup, Xiong, Huabao, Munasinghe, Jeeva, Yazawa, Itaru, O'Donovan, Michael J, Maximova, Olga A, Sharma, Suveena, Zhu, Jinfang, Wang, Hongsheng, Morse, Herbert C, Ozato, Keiko
• Format: Article
• Language: English
• Subjects: Autoimmune diseases; Deoxyribonucleic acid; Disease; DNA; Lymphocytes; NMR; Nuclear magnetic resonance; Rodents; Transcription factors
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2013.11.022

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 thatIrf8?/?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 ?v?8 integrin expression in APCs and activated TGF-? 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.