Zeng Zhutian’s Team identifies a Bladder-Blood Immune Barrier Constituted by Tissue Resident Macrophages
Source：Zeng Zhutian
2025-03-19
Sepsis has become a leading cause of death, accounting for approximately 20% of annual mortality globally. Nearly a quarter of sepsis cases result from urinary tract infections (UTIs), which primarily occur in the bladder, affecting approximately 150 million people worldwide each year, making UTIs one of the most prevalent bacterial infections. Effectively confining uropathogens in the bladder and preventing their dissemination into the bloodstream is crucial for mitigating the risk of sepsis.
On March 11, 2025, a study entitled "A bladder-blood immune barrier constituted by suburothelial perivascular macrophages restrains uropathogen dissemination" was published in Immunity, led by the research team of Professor Zeng Zhutian from the National Key Laboratory of Immune Response and Immunotherapy at the University of Science and Technology of China (USTC) and. This study identified and named a novel population of bladder resident macrophages, the suburothelial perivascular macrophages (suPVMs), and uncovered their critical role in preventing uropathogen dissemination into the bloodstream by releasing macrophage extracellular traps (METs). This newly discovered bladder-blood immune barrier provides valuable insights into the pathological mechanisms of urosepsis and potential strategies for prevention and treatment.
Discovery of suPVMs and Their Barrier Function
The study first analyzed the heterogeneity of bladder mucosal macrophages under homeostatic conditions and identified a unique subset of CX3CR1hi macrophages located beneath the urothelium and closely attached to abluminal surface of blood vessels. They were named as suPVMs (suburothelial perivascular macrophages). Using a clinically relevant uropathogenic Escherichia coli (UPEC) infection model, the research team further found that although UPEC rapidly breached the urothelial barrier and invaded the vascularized lamina propria during early infection, it did not enter the bloodstream or spread systemically. However, specific depletion of suPVMs resulted in significant UPEC dissemination from the bladder into the bloodstream, spreading to distant organs such as the liver and spleen, ultimately leading to bacteremia and multi-organ inflammation. These findings highlight the critical role of suPVMs in forming a bladder-blood immune barrier that restricts uropathogen dissemination.
METs: A Key Mechanism in Bladder Defense to UTIs
Using high-resolution real-time intravital microscopy, the researchers monitored the dynamic changes in suPVM morphology and behavior during early stage of UTI. Some suPVMs detached from blood vessel and released fibrous, DNA-rich structures containing citrullinated histones into the bladder mucosa. Further investigation identified that these structures were macrophage extracellular traps (METs). METs not only captured large numbers of UPEC bacteria within the urothelial layer, preventing their deeper invasion, but also were loaded with matrix metalloproteinase MMP13, which degraded the basement membrane, facilitating neutrophil infiltration and enhancing bacterial clearance.
This study challenges the conventional understanding of urinary mucosal immunity by identifying the bladder-blood immune barrier and elucidating its functional mechanisms. It provides a potential explanation for a long-standing paradox in UTI research: Why do most UTIs occur in the bladder, while urosepsis is predominantly caused by kidney infections? Furthermore, this study represents the first in vivo demonstration of macrophage ETosis leading to MET formation, offering a new perspective for exploring the function and fate of tissue-resident macrophages.
Dr. Lu Li, Associate Researcher at the First Affiliated Hospital of USTC, and Qiancheng Jiao, PhD student at the School of Life Sciences and Medicine, are the co-first authors of this paper. Professor Zeng Zhutian is the corresponding author. The study was conducted with support from collaborative teams led by Professors Tian Zhigang and Li Hai at USTC and was funded by the National Key R&D Program of China and the National Natural Science Foundation of China.
Article Link: https://doi.org/10.1016/j.immuni.2025.02.002
On March 11, 2025, a study entitled "A bladder-blood immune barrier constituted by suburothelial perivascular macrophages restrains uropathogen dissemination" was published in Immunity, led by the research team of Professor Zeng Zhutian from the National Key Laboratory of Immune Response and Immunotherapy at the University of Science and Technology of China (USTC) and. This study identified and named a novel population of bladder resident macrophages, the suburothelial perivascular macrophages (suPVMs), and uncovered their critical role in preventing uropathogen dissemination into the bloodstream by releasing macrophage extracellular traps (METs). This newly discovered bladder-blood immune barrier provides valuable insights into the pathological mechanisms of urosepsis and potential strategies for prevention and treatment.
Discovery of suPVMs and Their Barrier Function
The study first analyzed the heterogeneity of bladder mucosal macrophages under homeostatic conditions and identified a unique subset of CX3CR1hi macrophages located beneath the urothelium and closely attached to abluminal surface of blood vessels. They were named as suPVMs (suburothelial perivascular macrophages). Using a clinically relevant uropathogenic Escherichia coli (UPEC) infection model, the research team further found that although UPEC rapidly breached the urothelial barrier and invaded the vascularized lamina propria during early infection, it did not enter the bloodstream or spread systemically. However, specific depletion of suPVMs resulted in significant UPEC dissemination from the bladder into the bloodstream, spreading to distant organs such as the liver and spleen, ultimately leading to bacteremia and multi-organ inflammation. These findings highlight the critical role of suPVMs in forming a bladder-blood immune barrier that restricts uropathogen dissemination.
METs: A Key Mechanism in Bladder Defense to UTIs
Using high-resolution real-time intravital microscopy, the researchers monitored the dynamic changes in suPVM morphology and behavior during early stage of UTI. Some suPVMs detached from blood vessel and released fibrous, DNA-rich structures containing citrullinated histones into the bladder mucosa. Further investigation identified that these structures were macrophage extracellular traps (METs). METs not only captured large numbers of UPEC bacteria within the urothelial layer, preventing their deeper invasion, but also were loaded with matrix metalloproteinase MMP13, which degraded the basement membrane, facilitating neutrophil infiltration and enhancing bacterial clearance.
This study challenges the conventional understanding of urinary mucosal immunity by identifying the bladder-blood immune barrier and elucidating its functional mechanisms. It provides a potential explanation for a long-standing paradox in UTI research: Why do most UTIs occur in the bladder, while urosepsis is predominantly caused by kidney infections? Furthermore, this study represents the first in vivo demonstration of macrophage ETosis leading to MET formation, offering a new perspective for exploring the function and fate of tissue-resident macrophages.
Dr. Lu Li, Associate Researcher at the First Affiliated Hospital of USTC, and Qiancheng Jiao, PhD student at the School of Life Sciences and Medicine, are the co-first authors of this paper. Professor Zeng Zhutian is the corresponding author. The study was conducted with support from collaborative teams led by Professors Tian Zhigang and Li Hai at USTC and was funded by the National Key R&D Program of China and the National Natural Science Foundation of China.
Article Link: https://doi.org/10.1016/j.immuni.2025.02.002
