Krüppel-like Factor-4-Mediated Macrophage Polarization and Phenotypic Transitions Drive Intestinal Fibrosis in THP-1...

Area of Science:

• Gastroenterology and Immunology
• Molecular Biology and Cellular Mechanisms

Background:

• Biologic therapies have advanced inflammatory bowel disease (IBD) treatment, yet fibrosis-related strictures remain a clinical challenge.
• Understanding the molecular mechanisms driving intestinal fibrosis is crucial for developing novel therapeutic strategies.

Purpose of the Study:

• To investigate the role of Krüppel-like factor 4 (KLF4) in intestinal fibrosis.
• To explore the interplay between KLF4, macrophage polarization, cytokine expression, and stromal myofibroblasts in fibrosis development.
• To examine KLF4's influence on human small intestinal organoids.

Main Methods:

• Utilized THP-1 monocyte models to assess KLF4 expression and its effects on macrophage polarization and cytokine profiles.
• Conducted co-culture experiments with stromal myofibroblasts and conditioned macrophage media.
• Employed human induced pluripotent stem cell-derived small intestinal organoids to model in vivo responses.

Main Results:

• Different macrophage subtypes displayed distinct KLF4 expression patterns and functions.
• KLF4 knockdown altered cytokine expression, with M2b macrophages showing anti-fibrotic effects via IL-10.
• Macrophage-myofibroblast interactions promoted inflammatory phenotypes and upregulated fibrosis-associated IL-36α.

Conclusions:

• KLF4 plays a significant role in regulating macrophage polarization and mediating interactions crucial for intestinal fibrosis.
• The study provides insights into the complex interplay of cellular components and cytokines in fibrosis pathogenesis.
• Findings suggest potential therapeutic targets for mitigating fibrosis in IBD.