PARP1 promotes the release of HMGB1 increasing intestinal inflammation

Background and aims: Poly (ADP-ribose) polymerase (PARP), a protein family that includes PARP1, is involved in cellular processes such as DNA repair, genomic stability and cell death. In addition, PARP1 has been recently demonstrated to be involved in several inflammatory diseases, such as septic shock, asthma, atherosclerosis as well as in cancer. The alarmin High-Mobility Group Box 1 (HMGB1) exhibits various functions according to its subcellular location, which is finely conditioned by diverse post-translational modifications. High levels of fecal HMGB1 have been related to the presence of intestinal inflammation. Recent evidence suggests that PARP-1 induces the poly-ADP-ribosylation (PARylation) of HMGB1 and regulates its translocation to the cytoplasm. The aim of this study was to deeply investigate the relationship between PARP1 and HMGB1 in controlling intestinal inflammation. Methods: Dextran sodium sulphate (DSS) was used to induce a severe colitis in C57BL/6 WT or PARP-/- mice. 3D organoid cultures of intestinal stem cells harvested from biopsies of ulcerative colitis (UC) patients, were treated with cytomix (TNF + IFN) to induce inflammation. Results: Results show that PARP1-/- mice exhibit a less severe colitis compared to WT mice, as evidenced by the reduction of HMGB1 in serum and stool samples. 3D organoid cultures exposed to cytomix show increased levels of IL-1, IL8 and TNF as well as extracellular HMGB1. Interestingly, PARP1 specific inhibitor, PJ34, decreases the release of HMGB1. Conclusions: These data demonstrate that PARP1 contributes to HMGB1 release resulting in the promotion of inflammation. Thus, PARP1 could represent a novel target to reduce intestinal inflammation.