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

Extracellular High-mobility group box 1 (HMGB1) contributes to the pathogenesis of inflammatory disorders, including inflammatory bowel diseases (IBD). Poly (ADP-ribose) polymerase 1 (PARP1) has been recently reported to promote HMGB1 acetylation and its secretion outside cells. In this study, the relationship between HMGB1 and PARP1 in controlling intestinal inflammation was explored. C57BL6/J wild type (WT) and PARP1-/- mice were treated with DSS to induce acute colitis, or with the DSS and PARP1 inhibitor, PJ34. Human intestinal organoids, which are originated from ulcerative colitis (UC) patients, were exposed to pro-inflammatory cytokines (INFγ + TNFα) to induce intestinal inflammation, or coexposed to cytokines and PJ34. Results show that PARP1-/- mice develop less severe colitis than WT mice, evidenced by a significant decrease in fecal and serum HMGB1, and, similarly, treating WT mice with PJ34 reduces the secreted HMGB1. The exposure of intestinal organoids to pro-inflammatory cytokines results in PARP1 activation and HMGB1 secretion; nevertheless, the co-exposure to PJ34, significantly reduces the release of HMGB1, improving inflammation and oxidative stress. Finally, HMGB1 release during inflammation is associated with its PARP1-induced PARylation in RAW264.7 cells. These findings offer novel evidence that PARP1 favors HMGB1 secretion in intestinal inflammation and suggest that impairing PARP1 might be a novel approach to manage IBD.

Comments：

The study explores the relationship between PARP1 and HMGB1 in controlling intestinal inflammation, specifically in the context of inflammatory bowel diseases (IBD). The researchers used C57BL6/J wild type (WT) and PARP1-/- mice, as well as human intestinal organoids derived from ulcerative colitis (UC) patients, to investigate the effects of PARP1 inhibition on HMGB1 secretion and inflammation. The results indicate that PARP1 plays a significant role in promoting HMGB1 acetylation and secretion, and its inhibition through genetic knockout or pharmacological intervention can reduce the severity of colitis and improve inflammation and oxidative stress.

The researchers found that PARP1-/- mice exhibited less severe colitis than WT mice, as evidenced by a significant decrease in fecal and serum HMGB1. Similarly, treating WT mice with the PARP1 inhibitor PJ34 resulted in reduced HMGB1 secretion. In the human intestinal organoid model, exposure to pro-inflammatory cytokines resulted in PARP1 activation and HMGB1 secretion, while co-exposure to cytokines and PJ34 significantly reduced the release of HMGB1 and improved inflammation and oxidative stress.

Overall, these findings suggest that PARP1 plays a critical role in promoting HMGB1 secretion during intestinal inflammation and that targeting PARP1 might be a potential therapeutic approach for managing IBD. Additionally, this study highlights the importance of understanding the molecular mechanisms underlying inflammation and the potential for targeted interventions to improve disease outcomes.