TY - JOUR
T1 - The Transcription Factor IRF8 Activates Integrin-Mediated TGF-β Signaling and Promotes Neuroinflammation
AU - Yoshida, Yuko
AU - Yoshimi, Ryusuke
AU - Yoshii, Hiroaki
AU - Kim, Daniel
AU - Dey, Anup
AU - Xiong, Huabao
AU - Munasinghe, Jeeva
AU - Yazawa, Itaru
AU - O'Donovan, Michael J.
AU - Maximova, Olga A.
AU - Sharma, Suveena
AU - Zhu, Jinfang
AU - Wang, Hongsheng
AU - Morse, Herbert C.
AU - Ozato, Keiko
N1 - Funding Information:
We thank Alan Koretsky (NINDS) for his support and critical reading of the manuscript, Takayuki Ito and Makoto Horiuchi (UC, Davis), Ulrich Siebenlist (NIAID) for useful advice on experiments and reagents, and Mehrnoosh Abshari for assistance in cell sorting and in vitro experiments. This work was supported by the Intramural Program of NICHD, NIAID, and NINDS, National Institutes of Health.
PY - 2014/2/20
Y1 - 2014/2/20
N2 - 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 hasremained 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 Tcells, 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 thatfavored growth and maintenance of Th1 and Th17cells, 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.
AB - 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 hasremained 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 Tcells, 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 thatfavored growth and maintenance of Th1 and Th17cells, 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.
UR - http://www.scopus.com/inward/record.url?scp=84894280989&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2013.11.022
DO - 10.1016/j.immuni.2013.11.022
M3 - Article
C2 - 24485804
AN - SCOPUS:84894280989
SN - 1074-7613
VL - 40
SP - 187
EP - 198
JO - Immunity
JF - Immunity
IS - 2
ER -