Intestinal stroma guides monocyte differentiation to macrophages through GM-CSF

Area of Science:

• Gastroenterology
• Immunology
• Cell Biology

Background:

• Stromal cells are crucial for maintaining intestinal homeostasis and contribute to inflammatory bowel disease (IBD) pathogenesis.
• Understanding the specific stromal cell responses to inflammation is key to unraveling IBD mechanisms.

Purpose of the Study:

• To quantify the stromal cell response to inflammation in pediatric IBD.
• To identify subset-specific inflammatory responses within different intestinal segments and layers.
• To elucidate the role of stromal cells in guiding immune cell differentiation in the context of IBD.

Main Methods:

• Utilized a murine dynamic gut injury model for in vivo analysis.
• Performed human ex vivo transcriptomic, protein, and spatial analyses.
• Established primary human fibroblast-monocyte co-cultures to study cell-cell interactions.

Main Results:

• Identified co-localization of PDGFRA+CD142-/low fibroblasts and monocytes/macrophages in the intestine.
• Demonstrated that PDGFRA+CD142-/low fibroblasts promote monocyte differentiation into CCR2+CD206+ macrophages via GM-CSF.
• Observed that monocyte-derived CCR2+CD206+ macrophages resemble those found in pediatric IBD patients, exhibiting high PD-L1 and low GM-CSF receptor expression.

Conclusions:

• Stromal cells exhibit subset-specific inflammatory responses in pediatric IBD.
• The intestinal stroma plays a directive role in shaping intestinal macrophage differentiation.
• Targeting fibroblast-monocyte interactions could offer novel therapeutic strategies for IBD.