Inhibition of Interferon Regulatory Factor 4 Suppresses Th1 and Th17 Cell Differentiation and Ameliorates...

Multiple sclerosis (MS) is an autoimmune disease that is characterized by recurrent episodes of T-cell-mediated immune attack on central nervous system (CNS) myelin, leading to axon damage and progressive disability. Interferon regulatory factor 4 (IRF4) is expressed predominantly in the immune system and plays an important role in its development and function. Recent study demonstrated that IRF4 was critical for the generation of IL-17-producing Th17 cells. However, the effect of IRF4 on experimental autoimmune encephalomyelitis (EAE), an animal model of MS, needs to be further investigated. In our current study, inhibition of IRF4 with IRF4 siRNA (SiIRF4) decreases EAE scores and infiltration of Th1 and Th17 cells, but increases Treg infiltration. SiIRF4 inhibits Th1 and Th17 cell differentiation in vivo and in vitro. In our DC-T-cell coculture system, SiIRF4-treated DCs resulted in significantly less IFN-γ and IL-17 production from T cells. Next, we adoptively transfer CD11c(+) DCs from SiIRF4-treated mice into recipient mice and found that these CD11c(+) DCs ameliorated EAE. Furthermore, CD11c(+) DCs from SiIRF4-treated naive mice exhibited significantly reduced expression of pro-inflammatory cytokines TNF-α, IL-1β, IL-6 and IL-12/IL-23 (p40), and a corresponding increase in anti-inflammatory IL-10 expression. In conclusion, inhibition of IRF4 suppresses Th1 and Th17 cell differentiation and ameliorates EAE, via a direct regulation of DCs.