中性粒细胞胞外捕获器可保护肾脏免受上升型感染,是白细胞量筒检测呈阳性的必要条件

IF 15.8 1区 医学 Q1 CELL BIOLOGY Science Translational Medicine Pub Date : 2024-09-25 DOI:10.1126/scitranslmed.adh5090
Andrew P. Stewart, Kevin W. Loudon, Matthew Routledge, Colin Y. C. Lee, Patrick Trotter, Nathan Richoz, Eleanor Gillman, Robin Antrobus, James Mccaffrey, David Posner, Andrew Conway Morris, Fiona E. Karet Frankl, Menna R. Clatworthy
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引用次数: 0

摘要

下尿路感染(UTI)很常见,但很少并发肾盂肾炎。然而,防止感染扩展到肾脏的机制尚不清楚。在这里,我们在健康人的尿液中发现了中性粒细胞胞外捕获物(NET),它们在尿路中提供了一种抗菌防御策略。在将尿路致病性大肠杆菌接种到膀胱的体内小鼠UTI模型和体外人体尿液模型中,NETs与尿液调节蛋白相互作用,形成大网将细菌困住。在小鼠体内抑制肽基精氨酸脱氨酶 4 (PADI4)可阻断 NETosis,并导致膀胱炎发展为肾盂肾炎,这表明尿液中性粒细胞的 NETosis 起到了防止细菌进入肾脏的作用。对英国生物库数据的分析表明,在多项全基因组关联研究中,与类风湿性关节炎风险增加有关的 PADI4 基因变异与UTI 易感性的降低一直存在关联。最后,我们还发现,尿液浸量计检测白细胞酯酶在有完整的血液中性粒细胞存在的情况下呈阴性,但当中性粒细胞受刺激发生NET时则呈阳性,而这可以通过选择性抑制PADI4来防止,这表明该检测并不像人们长期以来认为的那样检测绝对的中性粒细胞数量,而是专门检测发生NETosis的中性粒细胞。这些发现强调了NETosis在预防泌尿道升天性感染中的作用,并加深了我们对医学中最常见的临床检验之一的理解。
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Neutrophil extracellular traps protect the kidney from ascending infection and are required for a positive leukocyte dipstick test
Lower urinary tract infection (UTI) is common but only rarely complicated by pyelonephritis. However, the mechanisms preventing extension to the kidney are unclear. Here, we identified neutrophil extracellular traps (NETs) in healthy human urine that provide an antibacterial defense strategy within the urinary tract. In both in vivo murine models of UTI where uropathogenic E. coli are inoculated into the bladder and ex vivo human urine models, NETs interacted with uromodulin to form large webs that entrapped the bacteria. Peptidyl arginine deiminase 4 (PADI4) inhibition in mice blocked NETosis and resulted in progression of cystitis into pyelonephritis, suggesting that NETosis of urinary neutrophils acts to prevent bacterial ascent into the kidney. Analysis of UK Biobank data revealed that genetic variants in PADI4 that associated with increased risk of rheumatoid arthritis in multiple genome-wide association studies were consistently associated with reduced susceptibility to UTI. Last, we showed that urine dipstick testing for leukocyte esterase was negative in the presence of intact blood neutrophils but became positive when neutrophils were stimulated to NET, and this could be prevented by selective PADI4 inhibition, demonstrating that this test does not detect absolute neutrophil count, as has long been assumed, but specifically detects neutrophils that have undergone NETosis. These findings highlight the role of NETosis in preventing ascending infections in the urinary tract and improve our understanding of one of the most common clinical tests in medicine.
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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