Cortactin deficiency causes increased RhoA/ROCK1-dependent actomyosin contractility, intestinal epithelial barrier...

Area of Science:

• Cell Biology
• Immunology
• Gastroenterology

Background:

• The intestinal epithelium is a key innate immune defense line.
• Epithelial barrier dysfunction characterizes inflammatory bowel diseases (IBD).
• The role of actin regulators like cortactin in epithelial barrier function is unclear.

Purpose of the Study:

• To investigate the role of cortactin in regulating intestinal epithelial barrier integrity.
• To determine if cortactin dysfunction contributes to IBD pathogenesis.

Main Methods:

• Utilized cortactin-knockout (KO) mice to assess intestinal barrier function.
• Analyzed tight junction protein expression (ZO-1, claudins, E-cadherin).
• Assessed actomyosin contractility, epithelial proliferation, and apoptosis.
• Induced colitis using dextran sulfate sodium (DSS) in KO mice.
• Examined cortactin expression in human colon tissues from healthy individuals and IBD patients.

Main Results:

• Cortactin deficiency in mice led to increased colon permeability with altered tight junction protein levels (decreased ZO-1, claudin-1, E-cadherin; increased claudin-2).
• Cortactin loss enhanced RhoA/ROCK1-dependent contractility, and ROCK1 inhibition restored barrier function.
• Cortactin deficiency increased epithelial proliferation but not apoptosis.
• Cortactin-KO mice showed heightened susceptibility to DSS-induced colitis, exhibiting severe tissue damage, edema, mucus deposition, and goblet cell depletion.
• Healthy human colon tissues showed cortactin co-localization with ZO-1 at epithelial junctions; IBD patients displayed reduced cortactin levels and disrupted co-localization.

Conclusions:

• Cortactin is a critical regulator of intestinal epithelial barrier integrity in vivo.
• Cortactin dysfunction contributes to IBD pathogenesis.
• Cortactin represents a potential therapeutic target for IBD treatment.