Innate immune overactivation hinders nuclear reprogramming through IFN-IFNAR1 axis

Abstract

Nuclear reprogramming to pluripotency holds great promise for regenerative medicine. However, innate immune overactivation may impair nuclear reprogramming efficiency but the underlying mechanism is not fully understood. Here we used mouse embryonic fibroblasts isolated from doxycycline-inducible OSKM transgenic mice as the nuclear reprogramming system and administered a high dosage of Polyinosinic polycytidylic acid (PIC) to stimulate TLR3 as the innate immune overactivation. PIC treatment reduced nuclear reprogramming efficiency. We identified that PIC treatment upregulated type I interferon transcription and secretion, IFNAR1 cell surface expression, and nuclear Stat1 level. Importantly, the introduction of Ifnar1 blocking antibody completely reversed this impaired nuclear reprogramming efficiency. Similarly, Ifn-β neutralizing antibody substantially ameliorated the impaired nuclear reprogramming efficiency caused by PIC treatment. Our data suggest that innate immune overactivation impairs nuclear reprogramming through the IFN-IFNAR1 axis. Blocking this signaling pathway can be used as a general strategy to enhance nuclear reprogramming efficiency.