Spermidine Suppresses Inflammatory DC Function by Activating the FOXO3 Pathway and Counteracts Autoimmunity

Area of Science:

• Immunology
• Metabolism
• Autoimmune Diseases

Background:

• Dendritic cell (DC) function is influenced by microenvironment and metabolism.
• Type I interferons (IFNs) promote DC responses to self-signals, contributing to autoimmunity.
• Metabolic adaptations during DC activation by IFNs are not well understood.

Purpose of the Study:

• To investigate the role of metabolites in IFN-primed DC function.
• To identify key metabolic changes impacting DC activation.
• To explore spermidine as a potential therapeutic agent for autoimmune diseases.

Main Methods:

• Dynamic metabolome screening of DCs.
• In vitro and in vivo experiments with spermidine supplementation.
• Analysis of FOXO3 activity and its role in mediating spermidine's effects.
• Mouse models of psoriasis-like skin inflammation.

Main Results:

• Spermidine levels decreased during IFN priming and TLR7 stimulation, coinciding with a shift from oxidative phosphorylation to glycolysis.
• Spermidine supplementation inhibited glycolysis and prevented DC overactivation.
• FOXO3 activity was modulated by metabolic changes, mediating spermidine's anti-inflammatory effects.
• In vivo spermidine administration reduced psoriasis-like symptoms in mice.

Conclusions:

• Metabolic reprogramming, including decreased spermidine and increased glycolysis, enhances DC responses.
• Spermidine acts as an anti-inflammatory agent by modulating DC metabolism and FOXO3 activity.
• Spermidine demonstrates therapeutic potential for autoimmune diseases such as psoriasis.