A bladder-blood immune barrier constituted by suburothelial perivascular macrophages restrains uropathogen dissemination.

Summary

This mechanistic study identifies suburothelial perivascular macrophages as a bladder–blood immune barrier that captures UPEC, maintains vascular integrity, and deploys METosis with MMP-13 to trap bacteria and recruit neutrophils. Monocyte-derived replenishment confers protection against recurrent UTIs, suggesting new strategies to prevent urosepsis.

Key Findings

• Identified suburothelial perivascular macrophages (suPVMs) that capture UPEC and preserve inflamed vessel integrity during acute cystitis.
• suPVMs undergo METosis to release macrophage extracellular DNA traps into the urothelium, sequestering bacteria and releasing MMP-13 to promote neutrophil transuroepithelial migration.
• Monocyte-derived replenishment of suPVMs after prior infection confers protection against recurrent UTIs, constituting a bladder–blood immune barrier that restrains dissemination.

Clinical Implications

While preclinical, the findings suggest avenues to prevent urosepsis by enhancing suPVM function, modulating METosis/MMP-13, or leveraging monocyte training/vaccination to bolster bladder barrier immunity.

Limitations

• Preclinical murine models; human validation is needed.
• Pathogen breadth and strain-specificity beyond UPEC require testing.

Future Directions

Validate suPVM signatures and METosis/MMP-13 pathways in human bladder tissue; test pharmacologic or vaccine strategies to enhance barrier function and reduce urosepsis.