Macrophage-endothelial cell crosstalk orchestrates neutrophil recruitment in inflamed mucosa

Area of Science:

• Immunology
• Cell Biology
• Gastroenterology

Background:

• Neutrophil mobilization is vital for host defense, requiring transendothelial migration (TEM) across endothelial cells (ECs).
• The initiation and termination mechanisms of TEM, particularly the role of macrophages, remain incompletely understood.

Purpose of the Study:

• To elucidate a novel mechanism by which vessel-associated macrophages regulate neutrophil TEM.
• To identify the molecular mediators and cellular interactions involved in initiating neutrophil recruitment to inflamed tissues.

Main Methods:

• Real-time intravital microscopy in CX3CR1-EGFP macrophage-reporter mice with LPS-induced intestinal inflammation.
• Whole-mount tissue imaging, flow cytometry, and macrophage depletion using anti-CSF1R antibody.
• Analysis of human clinical specimens, TNF-α knockout models, and co-culture systems.

Main Results:

• Macrophage association with vessels is critical for initiating neutrophil-endothelial cell adhesive interactions and subsequent TEM.
• Macrophage depletion eliminated ICAM-1 'hot spots', significantly impeding neutrophil migration.
• Macrophage-derived TNF-α signaling through the EC TNFR2 axis was identified as the key regulatory mechanism for PMN TEM.

Conclusions:

• Vessel-associated macrophages initiate neutrophil TEM by creating localized ICAM-1 hotspots.
• The macrophage-derived TNF-α and EC TNFR2 pathway is essential for regulating neutrophil trafficking in inflamed intestinal mucosa.
• These findings reveal clinically relevant mechanisms of macrophage-mediated immune cell recruitment.