α–Intercalated cells defend the urinary system from bacterial infection

作者：Neal Paragas, Ritwij Kulkarni, Max Werth, Kai M. Schmidt‐Ott, Catherine S. Forster, Rong Deng, Qingyin Zhang, Eugenia Singer, Alexander D. Klose, Tian Shen, Kevin P. Francis, Sunetra Ray, Soundarapandian Vijayakumar, Samuel L. Seward, Mary E. Bovino, Katherine Xu, Yared Takabe, Fábio E. Amaral, Sumit Mohan, Rebecca Wax, Kaitlyn Corbin, Simone Sanna‐Cherchi, Kiyoshi Mori, Lynne Johnson, Thomas L. Nickolas, Vivette D. D’Agati, Chyuan‐Sheng Lin, Andong Qiu, Qais Al‐Awqati, Adam J. Ratner, Jonathan Barasch · 发表于：Journal of Clinical Investigation · 年份：2014 · DOI：10.1172/jci71630 · 被引用次数：153 · 研究领域：Pediatric Urology and Nephrology Studies、Acute Kidney Injury Research、Clinical Nutrition and Gastroenterology

α-Intercalated cells (A-ICs) within the collecting duct of the kidney are critical for acid-base homeostasis. Here, we have shown that A-ICs also serve as both sentinels and effectors in the defense against urinary infections. In a murine urinary tract infection model, A-ICs bound uropathogenic E. coli and responded by acidifying the urine and secreting the bacteriostatic protein lipocalin 2 (LCN2; also known as NGAL). A-IC-dependent LCN2 secretion required TLR4, as mice expressing an LPS-insensitive form of TLR4 expressed reduced levels of LCN2. The presence of LCN2 in urine was both necessary and sufficient to control the urinary tract infection through iron sequestration, even in the harsh condition of urine acidification. In mice lacking A-ICs, both urinary LCN2 and urinary acidification were reduced, and consequently bacterial clearance was limited. Together these results indicate that A-ICs, which are known to regulate acid-base metabolism, are also critical for urinary defense against pathogenic bacteria. They respond to both cystitis and pyelonephritis by delivering bacteriostatic chemical agents to the lower urinary system.