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.

中文翻译：

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中性粒细胞细胞外陷阱可保护肾脏免受上行性感染，并且是白细胞试纸试验阳性所必需的


下尿路感染 （UTI） 很常见，但很少并发肾盂肾炎。然而，阻止扩散到肾脏的机制尚不清楚。在这里，我们在健康人尿液中鉴定了中性粒细胞细胞外陷阱 （NETs），它们在尿路内提供抗菌防御策略。在尿路感染的体内小鼠模型中，尿路致病性大肠杆菌接种到膀胱中，以及离体人尿液模型中，NETs 与尿调节蛋白相互作用，形成捕获细菌的大网。小鼠肽基精氨酸脱亚胺酶 4 （PADI4） 抑制阻断了 NETosis 并导致膀胱炎进展为肾盂肾炎，表明尿中性粒细胞的 NETosis 起到防止细菌上升到肾脏的作用。对英国生物样本库数据的分析显示，在多项全基因组关联研究中，与类风湿性关节炎风险增加相关的 PADI4 遗传变异始终与对 UTI 的易感性降低相关。最后，我们表明，在存在完整血液中性粒细胞的情况下，白细胞酯酶的尿液试纸检测为阴性，但当中性粒细胞被刺激到 NET 时变为阳性，这可以通过选择性 PADI4 抑制来预防，证明该测试并不像长期以来假设的那样检测绝对中性粒细胞计数，而是特异性检测经历 NETosis的中性粒细胞。这些发现强调了 NETosis 在预防尿路上行感染方面的作用，并提高了我们对医学中最常见的临床测试之一的理解。