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Disrupting of IGF2BP3-stabilized CLDN11 mRNA by TNF-α increases intestinal permeability in obesity-related severe

Lihui Lin1, Yansong Lin2, Xianwen Guo1

  • 1Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P. R. China.

Molecular Medicine (Cambridge, Mass.)
|January 25, 2025
PubMed
Abstract

Insights

Claudin 11 (CLDN11) helps regulate intestinal permeability in obesity-related severe acute pancreatitis (SAP). Tumor necrosis factor-alpha (TNF-α) disrupts this by reducing CLDN11 mRNA stability, leading to increased intestinal permeability and pancreatitis.

Area of Science:

  • Gastroenterology
  • Molecular Biology
  • Pathophysiology

Background:

  • Obesity is a key risk factor for severe acute pancreatitis (SAP), often linked to increased intestinal permeability.
  • Claudin 11 (CLDN11), a tight junction protein, influences barrier function, but its role in obesity-related SAP intestinal permeability is unknown.

Purpose of the Study:

  • To investigate the role and mechanism of CLDN11 in intestinal permeability during obesity-related SAP.
  • To explore the potential of targeting the CLDN11 pathway for therapeutic intervention.

Main Methods:

  • Evaluated intestinal permeability and CLDN11 expression in experimental obesity-related SAP models.
  • Utilized recombinant adeno-associated virus for CLDN11 manipulation and assessed its effects.
  • Investigated the interaction between CLDN11 mRNA and IGF2BP3 protein using bioinformatics and experimental validation.
  • Examined the impact of tumor necrosis factor-alpha (TNF-α) on the IGF2BP3/CLDN11 axis in Caco-2 cells and in vivo.

Main Results:

  • CLDN11 expression was downregulated in intestinal epithelial cells of experimental obesity-related SAP.
  • Exogenous CLDN11 restoration reduced intestinal epithelial permeability and pancreatic inflammation.
  • Overexpression of CLDN11 decreased paracellular permeability, while knockdown increased it.
  • IGF2BP3 was identified as a regulator of CLDN11 mRNA stability.
  • TNF-α downregulated both IGF2BP3 and CLDN11; anti-TNFα therapy improved intestinal barrier function and reduced pancreatitis.

Conclusions:

  • CLDN11 plays a crucial role in regulating intestinal permeability in obesity-related SAP.
  • Increased TNF-α impairs the stability of IGF2BP3-dependent CLDN11 mRNA, contributing to the pathophysiology of obesity-related SAP.
Keywords:
CLDN11IGF2BP3Intestinal permeabilityObesitySevere acute pancreatitisTNF-α

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