IL-10-STAT3 axis preserves epithelial mitochondrial homeostasis during bacterial challenge

Area of Science:

• Gastroenterology and Immunology
• Mitochondrial Biology
• Cellular Pathology

Background:

• Inflammatory bowel disease (IBD) pathogenesis involves mitochondrial dysfunction.
• The pathobiont adherent-invasive Escherichia coli (AIEC) disrupts epithelial mitochondrial integrity and barrier function.
• Interleukin-10 (IL-10) is crucial for maintaining enteric homeostasis.

Purpose of the Study:

• To investigate the protective role of IL-10 against AIEC-induced mitochondrial dysfunction in the gut epithelium.
• To elucidate the molecular mechanisms underlying IL-10's protective effects, focusing on STAT3 signaling.

Main Methods:

• Utilized human colon-derived T84 epithelial cells and colonic organoids.
• Infected cells and organoids with AIEC LF82.
• Assessed mitochondrial function (membrane potential, oxygen consumption rate, network analysis) and barrier integrity.
• Investigated STAT3 phosphorylation at serine 727 (S727) and tyrosine 705 (Y705) using pharmacological inhibitors (ERK, JAK) and STAT3 mutants.
• Compared IL-10 effects with IL-22.

Main Results:

• IL-10 pretreatment/cotreatment reduced AIEC-induced mitochondrial fragmentation and dysfunction in organoids and T84 cells.
• IL-10 preserved epithelial barrier integrity.
• IL-10 increased STAT3 phosphorylation at S727, dependent on ERK activation.
• STAT3 S727 phosphorylation was essential for IL-10's protective mechanism, as shown by STAT3 S727A mutant studies.
• IL-22, activating STAT3 Y705, did not prevent mitochondrial dysfunction.

Conclusions:

• IL-10 protects gut epithelial homeostasis against AIEC by maintaining mitochondrial integrity.
• The mechanism involves ERK-dependent STAT3 phosphorylation at S727, crucial for mitochondrial function.
• This IL-10-mediated pathway preserves epithelial barrier function, offering a potential therapeutic target for IBD.