Background: Intestinal barrier dysfunction and persistent inflammatory response are key pathophysiologic features of ulcerative colitis (UC). High mobility group box‐1 protein (HMGB1), an important inflammatory mediator and immunomodulatory factor, has been shown to be involved in the pathogenesis of UC. However, the association between HMGB1 and intestinal barrier dysfunction is unclear. Methods: In this study, we investigated the mechanism of HMGB1 driving intestinal barrier damage by integrating clinical data, animal models, and cellular experiments in UC. First, HMGB1 levels and its correlation with intestinal barrier protein expression in UC patients were verified based on Gene Expression Omnibus (GEO) dataset GSE75214 analysis and western blotting (WB) assay. Subsequently, colitis was induced in C57BL/6J mice using dextran sodium sulfate (DSS) and intervened with dipotassium glycyrrhizinate (DPG), and the effects of HMGB1 on colonic inflammation, ferroptosis, and intestinal barrier were assessed by histopathological scoring, qRT‐PCR, enzyme‐linked immunosorbent assay (ELISA), WB assay, immunofluorescence, and transmission electron microscopy (TEM) examination. Lastly, the influence of HMGB1 on ferroptosis‐related genes expression, TLR4/NF‐κB/GPX4 pathway activation and intestinal barrier damage were revealed by transepithelial electrical resistance (TEER) value measures, FITC‐dextran permeability detections, qRT‐PCR, and WB assays in vitro Caco‐2 cell models. Results: HMGB1 expression was significantly elevated in colonic tissues of UC patients (especially in active stage), and was negatively correlated with barrier protein expression. In DSS‐induced colitis mouse model, HMGB1 upregulation accompanied by changes in TLR4, NF‐κB, and GPX4 expression and ferroptosis‐related genes upregulation, while inhibition of HMGB1 attenuated inflammation, restored barrier function, and reversed ferroptosis. Moreover, cellular experiments further confirmed HMGB1 induced ferroptosis and intestinal barrier damage in Caco‐2 cells via the TLR4/NF‐κB/GPX4 pathway. Conclusion: Our results suggest that HMGB1 drives ferroptosis through the TLR4/NF‐κB/GPX4 signaling pathway, thereby exacerbating intestinal inflammation and barrier damage in UC. Targeting this pathway may provide a novel therapeutic strategy for UC.

Zhang Q, et al. Yonsei Med J. 2022 Feb;63(2):148-157. https://doi.org/10.3349/ymj.2022.63.2.148

Connective tissue disease (CTD) patients may suffer from pulmonary arterial hypertension (PAH), a serious complication, and anti-U1 ribonucleoprotein (RNP) antibodies can be used as a potential indicator for the development and prognosis of CTD-associated PAH (CTD-PAH). However, there are still some controversies; thus, a systematic review and meta-analysis were performed. We searched PubMed, Embase, Cochrane Library, and Scopus for eligible studies and assessed their quality using Newcastle–Ottawa scales or Agency for Healthcare Research and Quality indicators according to the type of research. Odds ratio (OR) was adopted as a measure of effect in risk factor analysis, and hazard ratio (HR) was adopted for prognostic factor analysis. Publication bias was evaluated using the Egger’s test. Thirteen studies were finally included. Anti-U1 RNP antibody was proved as a risk factor for PAH among CTD patients (OR = 5.30, 95%CI 2.96–9.48, p < 0.05) and a protective factor against mortality among CTD-PAH patients (HR = 0.55, 95%CI 0.36–0.83, p < 0.05). CTD patients with positive anti-U1 RNP antibodies are at high risk for PAH, so routine screening examinations, including echocardiography, are recommended. Additionally, anti-U1 RNP positivity has been linked to decreased mortality in patients with CTD-PAH.

Ulcerative colitis (UC) is characterized by inflammatory damage of the intestinal epithelium, contributed by activation of Piezo-type mechanosensitive ion channel component 1 (Piezo1) and dysregulation of zinc homeostasis, critically maintained by zinc transporter 1 (ZnT1). Interactions between Piezo1 and ZnT1-mediated zinc homeostasis and effects on barrier function during colitis were investigated in this study. Inflammation-induced barrier disruption was modeled in vivo using dextran sulfate-treated mice and in vitro using lipopolysaccharide-treated Caco-2 cells. Intestinal epithelial cell (IEC)-specific Piezo1 knockout in mice, small interfering RNA-mediated silencing, Piezo1 agonist and antagonist, zinc ion (Zn ²⁺ ) supplement and chelator in Caco-2 cells were utilized to manipulate activities of Piezo1 and ZnT1. Suppression of Piezo1 in IECs alleviated inflammation-induced barrier damage in vitro and in vivo. Bioinformatic analysis of UC patient datasets revealed an association between Piezo1 and zinc homeostasis and verified by elevated Piezo1 and ZnT1 expressions observed in both human UC and murine colitis samples. Suppression of Piezo1 led to ZnT1 downregulation in vitro and in vivo . Piezo1 activation caused enhanced Zn ²⁺ efflux and intracellular Zn ²⁺ depletion while Piezo1 inhibition led to Zn ²⁺ accumulation. Effects of zinc supplementation and chelation were consistent with the view that ZnT1 inhibition alleviated barrier disintegration. Our findings revealed that Piezo1 affected ZnT1-mediated zinc homeostasis in IECs. Piezo1 suppression downregulated ZnT1 expression, attenuating intracellular zinc depletion caused by excessive Zn ²⁺ efflux and relieved intestinal barrier disruption, indicating that Targeting the Piezo1-ZnT1-zinc signaling axis presents a promising therapeutic strategy for UC. Graphical Abstract Piezo1-activation exacerbates inflammation-induced intestinal barrier disruption by triggering Ca ²⁺ influx which upregulates ZnT1-mediated Zn ²⁺ efflux resulting in IECs Zn ²⁺ dyshomeostasis, and this disruption can be rescued by Piezo1 suppression. The figure was generated by adobe illustrator.