RADX protects against intestinal inflammation by restraining IFI16-mediated innate immunity

Area of Science:

• Genetics
• Immunology
• Gastroenterology

Background:

• Genomic instability is elevated in inflammatory bowel disease (IBD) patients.
• The direct role of genomic instability in IBD pathogenesis is not fully understood.

Purpose of the Study:

• To investigate the role of RADX in regulating intestinal inflammation and innate immune responses.
• To elucidate the mechanism by which RADX controls DNA damage sensing in the gut.
• To explore the therapeutic potential of targeting RAD51 in IBD.

Main Methods:

• Identification of RADX as a regulator of replication fork stability and antagonist to RAD51.
• Assessment of RADX deficiency in experimental colitis models.
• Investigation of the interaction between RADX, single-stranded DNA (ssDNA), and the DNA sensor IFI16.
• Analysis of RADX variants in IBD patients and their association with disease markers.
• Evaluation of RAD51 inhibition using RI-1 in colitis models.

Main Results:

• RADX deficiency exacerbates experimental colitis, mediated primarily by macrophages.
• RADX prevents IFI16-mediated activation of NF-κB signaling and inflammasome assembly by limiting ssDNA accumulation.
• IBD-associated RADX variants correlate with reduced RADX expression, increased DNA damage signaling, and elevated IL-1β levels.
• Pharmacological inhibition of RAD51 with RI-1 ameliorates colitis in mice.

Conclusions:

• RADX acts as a critical suppressor of intestinal inflammation by limiting innate immune sensing of replication-associated DNA damage.
• A RADX-IFI16 checkpoint restrains pathogenic innate immune activation, linking genome instability to IBD.
• Modulation of replication stress, specifically RAD51 inhibition, represents a potential therapeutic strategy for IBD.