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Investigating Intestinal Barrier Breakdown in Living Organoids
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Downregulated KLF4, induced by m6A modification, aggravates intestinal barrier dysfunction in inflammatory bowel
Xingchao Zhu1,2,3, Jiayu Wang1,2,3, Huan Zhang1,3
1Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 178 East Ganjiang Road, Suzhou, 215000, China.
Cellular and Molecular Life Sciences : CMLS
|November 29, 2024
Summary
Krüppel-like factor 4 (KLF4) is decreased in inflammatory bowel disease (IBD), worsening intestinal epithelial barrier (IEB) injury. Targeting KLF4 shows promise for IBD treatment by restoring IEB function.
Area of Science:
- Gastroenterology
- Molecular Biology
- Immunology
Background:
- Krüppel-like factor 4 (KLF4) is a transcription factor with diverse biological roles.
- Its specific function in regulating the intestinal epithelial barrier (IEB) during inflammatory bowel disease (IBD) remains underexplored.
Purpose of the Study:
- To investigate the role of KLF4 in maintaining the intestinal epithelial barrier (IEB) integrity in inflammatory bowel disease (IBD).
- To elucidate the underlying mechanisms by which KLF4 influences IEB function and colitis pathology.
- To explore KLF4 as a potential therapeutic target for IBD.
Main Methods:
- Analysis of KLF4 expression in IBD patients and colitis models using bioinformatics, immunohistochemistry, and Western blot.
- In vivo validation of KLF4's role in colitis using shRNA-mediated knockdown in mouse models (DSS and TNBS induced).
- In vitro and in vivo assessment of KLF4's impact on trans-epithelium electrical resistance (TEER), paracellular permeability, apoptosis, and apical junction complex (AJC) proteins.
- Investigation of m6A modification's effect on KLF4 expression using MeRIP and RIP assays.
Main Results:
- KLF4 expression is significantly reduced in IBD patients and negatively correlates with inflammation.
- KLF4 deficiency exacerbates colitis by compromising IEB integrity, increasing apoptosis, and reducing AJC proteins.
- KLF4 upregulates AJC proteins, inhibits apoptosis by reducing ROS and pro-inflammatory cytokines.
- m6A modification (METTL3/ALKBH5/YTHDF2) decreases KLF4 expression.
- KLF4 inducer APTO-253 shows synergistic effects with mesalazine on IEB function.
Conclusions:
- KLF4 is a critical regulator of intestinal epithelial barrier (IEB) integrity.
- Downregulation of KLF4 contributes to the pathogenesis of inflammatory bowel disease (IBD).
- Therapeutic strategies targeting KLF4 represent a promising avenue for IBD treatment.
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