Oxidative Stress-Induced HMGB1 Translocation in Myenteric Neurons Contributes to Neuropathy in Colitis

Abstract

High-mobility group box 1 (HMGB1) is a damage-associated molecular pattern released by dying cells to stimulate the immune response. During cell death, HMGB1 is translocated from the nucleus to the cytoplasm and passively released. High levels of secreted HMGB1 are observed in the faeces of inflammatory bowel disease (IBD) patients, indicating its role in IBD pathophysiology and potential as a non-invasive IBD biomarker. HMGB1 is important in regulating neuronal damage in the central nervous system; its pathological activity is intertwined with oxidative stress and inflammation. In this study, HMGB1 expression in the enteric nervous system and its relevance to intestinal neuroinflammation is explored in organotypic cultures of the myenteric plexus exposed to oxidative stimuli and in Winnie mice with spontaneous chronic colitis. Oxidative stimuli induced cytoplasmic translocation of HMGB1 in myenteric neurons in organotypic preparations. HMGB1 translocation correlated with enteric neuronal loss and oxidative stress in the myenteric ganglia of Winnie mice. Inhibition of HMGB1 by glycyrrhizic acid ameliorated HMGB1 translocation and myenteric neuronal loss in Winnie mice. These data highlight modulation of HMGB1 signalling as a therapeutic strategy to reduce the consequences of enteric neuroinflammation in colitis, warranting the exploration of therapeutics acting on the HMGB1 pathway as an adjunct treatment with current anti-inflammatory agents.

Bone marrow-derived mesenchymal stem cells mitigate chronic colitis and enteric neuropathy via anti-inflammatory and anti-oxidative mechanisms

“…Local oxidative stress is a primary driver of enteric neuropathy during intestinal inflammation 26 , 39 . To explore whether the presence of oxidative stress could be determined on the gene expression level in Winnie mice, gene sets associated with oxidative stress were curated from several databases to perform GSEA.…”

“…Cytoplasmic translocation and release of the redox-sensitive cytokine HMGB1 have been associated with oxidative stress during neuropathy of the CNS and ENS 26 , 41 . Considering that BM-MSCs were previously demonstrated to reduce oxidative stress in the myenteric neurons of Winnie mice, in vitro cultures were used to investigate the effect of BM-MSCs on oxidative stress-induced HMGB1 translocation.…”

“…HMGB1 plays a crucial role in the regulation of inflammation, acting as both a pro-inflammatory cytokine and a danger signaling molecule. It is released by necrotic cells and has been shown to contribute to neuropathies in experimental colitis 26 . Here we demonstrate that by targeting molecules such as HMGB1 we can unlock the therapeutic potential of MSCs through antioxidant and anti-inflammatory mechanisms.…”

Advanced Glycation End-Products and Their Effects on Gut Health

“…Particularly, increased interaction between RAGE and S100 proteins (S100A, S100A9, and S100A12) is associated with increased inflammation [ 79 , 80 ], contributing to worsen the pathogenesis of IBD [ 81 , 82 , 83 , 84 , 85 , 86 ]. Similarly, HMGB1 is another ligand binding to RAGE [ 80 ] and known to be a biomarker of IBD in numerous animal studies [ 87 , 88 , 89 ] and human studies [ 90 , 91 ]. There is also evidence that AGEs increase the expression of S100 proteins [ 92 ] and the activation of HMGB1 signals [ 93 ] to induce increased inflammation.…”

Transcriptomic analysis of differentially expressed genes in the Winnie mouse model of chronic colitis

“…For RNA sequencing, similar sections of distal colon segments were collected from each mouse, immediately placed into liquid nitrogen, and stored at -80 ºC until RNA extraction was performed. For histological analysis, distal colon tissues were removed, cut along the mesenteric border, cleared of contents, xed in Zamboni's xative for 24 hours, and embedded in the optimum cutting temperature (OCT) compound (Tissue Tek, CA, USA) and frozen in liquid nitrogen-cooled isopentane [50,51] Histology Distal colon tissue sections (15 µm thickness) were cut using a cryostat (Leica, Germany) and processed for hematoxylin and eosin or Alcian blue staining. Sections were mounted on glass slides with distrene plasticiser xylene.…”