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

Abstract

Urinary tract infections (UTIs) predominantly occur in the bladder and can potentially progress into life-threatening sepsis if uropathogens spread unconstrainedly into the bloodstream. Here, we identified a subset of suburothelial perivascular macrophages (suPVMs) in the bladder that exerted a pivotal barrier function to prevent systemic bacterial dissemination during acute cystitis. During the initial phase of uropathogenic Escherichia coli (UPEC) infection, suPVMs actively captured UPEC invading the laminal propria and maintained the integrity of inflamed vessels. They subsequently underwent METosis to expel macrophage extracellular DNA traps (METs) into the urothelium to sequester bacteria within this avascular compartment. Matrix metallopeptidase-13 was released along with METs to promote neutrophil transuroepithelial migration. Replenished suPVMs from monocytes following a prior infection were functionally competent to confer protection against recurrent UTIs. Our study thus uncovers a bladder-blood immune barrier in restraining uropathogen dissemination, which could have implications for the prevention and treatment of urosepsis.

Keywords: METs; MMP13; bacteremia; extracellular DNA traps; intravital imaging; neutrophils; perivascular macrophages; tissue-resident macrophages; urinary tract infections.