SIGIRR Alleviates Intestinal Mucosal Damage in Severe Acute Pancreatitis via the TLR4 Signaling Pathway.

BACKGROUND & AIMS: Intestinal barrier dysfunction plays an important role in the development of severe acute pancreatitis (SAP). The aim of our study was to investigate the role of single immunoglobulin IL-1 receptor-related molecule (SIGIRR) and Toll-like receptor-4 (TLR4) signaling pathways in SAP intestinal barrier dysfunction. METHODS: Intestinal epithelial monolayer barrier model were established by using Caco2 and HIEC cells. The effects of lipopolysaccharide or ascites fluids from patients with SAP on intestinal epithelial barrier function were assessed. Intestinal epithelial cells and mouse models with SIGIRR overexpression and knockdown were constructed to explore the role of SIGIRR on the intestinal inflammation and the TLR4 signaling pathway. RESULTS: SIGIRR expression was decreased in both intestinal epithelial cells and intestinal tissues during SAP. Overexpression of SIGIRR in intestinal epithelial cells reduced inflammation and enhanced intestinal barrier function, as evidenced by measurements such as electrical resistance and fluorescein permeability. In vivo, SIGIRR overexpression reduced intestinal mucosal injury in SAP and inhibited the TLR4 signaling pathway, whereas SIGIRR knockdown worsened these effects. Additionally, SIGIRR overexpression influenced gut microbiota composition, encouraging the growth of beneficial species and suppressing harmful pathogens. CONCLUSIONS: SIGIRR plays a protective role in SAP by preserving intestinal barrier integrity and negatively regulating the TLR4 signaling pathway. Targeting SIGIRR offers a novel approach for improving SAP.