PARP1 Activation Induces HMGB1 Secretion Promoting Intestinal Inflammation in Mice and Human Intestinal Organoids

Area of Science:

• Immunology
• Gastroenterology
• Molecular Biology

Background:

• Extracellular High-mobility group box 1 (HMGB1) is implicated in inflammatory disorders like inflammatory bowel diseases (IBD).
• Poly (ADP-ribose) polymerase 1 (PARP1) has been identified as a promoter of HMGB1 acetylation and secretion.

Purpose of the Study:

• To investigate the role of the HMGB1-PARP1 interaction in the development of intestinal inflammation.
• To explore the therapeutic potential of targeting PARP1 in IBD.

Main Methods:

• Utilized C57BL6/J wild type (WT) and PARP1 knockout (PARP1-/-) mice models of acute colitis induced by dext For sulfate (DSS).
• Administered the PARP1 inhibitor PJ34 to WT mice and human ulcerative colitis (UC) organoids exposed to pro-inflammatory cytokines (INFγ + TNFα).
• Assessed HMGB1 levels, inflammation markers, and oxidative stress in vivo and in vitro.

Main Results:

• PARP1-/- mice exhibited significantly reduced colitis severity and lower HMGB1 levels compared to WT mice.
• PJ34 treatment decreased HMGB1 secretion and ameliorated colitis in WT mice and inflammation/oxidative stress in human UC organoids.
• HMGB1 release during inflammation was directly linked to PARP1-induced PARylation in RAW264.7 cells.

Conclusions:

• PARP1 plays a crucial role in promoting HMGB1 secretion during intestinal inflammation.
• Inhibition of PARP1 represents a promising therapeutic avenue for managing inflammatory bowel diseases.