Innate immune overactivation hinders nuclear reprogramming through IFN-IFNAR1 axis.

Area of Science:

• Stem cell biology
• Immunology
• Regenerative medicine

Background:

• Nuclear reprogramming to pluripotency is crucial for regenerative medicine.
• Innate immune responses, particularly overactivation, can impede reprogramming efficiency.
• The precise mechanisms linking innate immunity to impaired reprogramming remain unclear.

Purpose of the Study:

• To investigate the mechanism by which innate immune overactivation impairs nuclear reprogramming.
• To identify potential therapeutic targets for enhancing reprogramming efficiency.

Main Methods:

• Utilized doxycycline-inducible OSKM transgenic mouse embryonic fibroblasts for nuclear reprogramming.
• Stimulated innate immune response using Polyinosinic polycytidylic acid (PIC) to activate TLR3.
• Assessed reprogramming efficiency, type I interferon (IFN) levels, IFNAR1 expression, and Stat1 activation.
• Employed IFNAR1 blocking antibodies and IFN-β neutralizing antibodies to evaluate pathway involvement.

Main Results:

• PIC treatment significantly reduced nuclear reprogramming efficiency.
• PIC-induced immune overactivation upregulated type I IFN transcription, secretion, IFNAR1 expression, and nuclear Stat1.
• Blocking IFNAR1 or neutralizing IFN-β fully reversed the PIC-mediated impairment of reprogramming.
• The findings implicate the IFN-IFNAR1 axis in the detrimental effects of innate immune overactivation on reprogramming.

Conclusions:

• Innate immune overactivation impairs nuclear reprogramming via the interferon-IFNAR1 signaling axis.
• Targeting the IFN-IFNAR1 pathway represents a promising strategy to enhance nuclear reprogramming efficiency for regenerative medicine applications.