Inhibition of Interferon Regulatory Factor 4 Attenuates Acute Liver Allograft Rejection in Mice

Acute liver allograft rejection is a serious complication after liver transplantation. Interferon regulatory factor 4 (IRF4) is expressed predominantly in the immune system and plays an important role in its development and function. However, the role of IRF4 in liver transplantation has never been investigated. In our current study, to evaluate the effect of IRF4 inhibition on recipient survival, IRF4 siRNA, or control siRNA, or PBS was injected into the liver allograft recipients through caudal vein. The survival time of mice treated with IRF4 siRNA (MST = 31.5 days) was prolonged significantly compared with that of mice treated with PBS (MST = 6 days) or control siRNA (MST = 6.5 days) (P < 0.001). IRF4 siRNA treatment displays lower induction of pro-inflammatory levels, including TNF-α, IL-6 and IFN-γ, and higher induction of anti-inflammatory IL-10 levels. Administration of anti-IL-10 into IRF4 siRNA-treated mice resulted in shortened allograft survival and increased rejection scores. Furthermore, IRF4 inhibition promotes M2 macrophage differentiation in vivo and in vitro. And inhibition of macrophages with GdCl3 reverses the prolonged liver allograft survival and decreased liver rejection scores induced by IRF4 siRNA. In conclusion, inhibition of IRF4 attenuates acute liver allograft rejection in mice, and this is associated with promoted M2 macrophage differentiation.