USTC identifies a bladder-blood immune barrier mediated by tissue-resident macrophages

A research team led by Prof. ZENG Zhutian from the University of Science and Technology of China (USTC) identified and named a novel population of bladder-resident macrophages, termed suburothelial perivascular macrophages (suPVMs), which can prevent hematogenous dissemination of uropathogens by releasing macrophage extracellular traps (METs). This finding has been published in Immunity.

Bladder infections, commonly known as urinary tract infections (UTIs), affect approximately 150 million people worldwide each year, making them one of the most prevalent bacterial infections. While UTIs typically remain localized in the bladder, bacteria can sometimes cross into the bloodstream, leading to systemic infection. Nearly a quarter of sepsis cases originate from UTIs, but how the bladder prevents most infections from spreading into the blood has puzzled scientists until now.

By analyzing the heterogeneity of bladder mucosal macrophages under homeostatic conditions, the researchers identified a novel subpopulation of CX3CR1^hi macrophages localized beneath the urothelium and closely associated with the outer walls of blood vessels. They named this population suburothelial perivascular macrophages (suPVMs). Utilizing a model of urinary tract infection induced by uropathogenic Escherichia coli (UPEC), the team further investigated the function of suPVMs. Their findings demonstrated that although UPEC can initially breach the urothelial barrier and invade the highly vascularized lamina propria, it fails to enter the bloodstream and disseminate systemically.

However, targeted depletion of suPVMs significantly promoted the translocation of UPEC from the bladder into the bloodstream, leading to bacterial dissemination to distant organs such as the liver and spleen, resulting in bacteremia and systemic inflammation. These findings show that suPVMs form a bladder-blood immune barrier that prevents uropathogens from spreading.

Using high-resolution real-time intravital imaging, the researchers observed morphological and behavioral changes in suPVMs during the early stages of UTI. Some suPVMs detached from the vascular walls and released DNA- and citrullinated histone-enriched fibrous structures into the urothelial region. Further investigations confirmed that these structures were macrophage extracellular traps (METs). METs not only capture large amounts of UPEC within the urothelial layer, preventing bacterial invasion into deeper bladder tissues, but also facilitate neutrophil infiltration by degrading the basement membrane via matrix metalloproteinase MMP13, enhancing bacterial clearance.

This study expands the traditional understanding of mucosal immunity in the urinary tract by unveiling the presence and functional mechanisms of the bladder-blood immune barrier. The findings explain why UTIs predominantly occur in the bladder, whereas urosepsis is primarily associated with kidney infections. Furthermore, this study provides the first in vivo evidence of macrophage ETosis and the formation of METs, opening new avenues for exploring the functional roles and fate of tissue-resident macrophages.