α-Intercalated cells defend the urinary system from bacterial infection

• Published in: The Journal of clinical investigation Vol. 124; no. 7; pp. 2963 - 2976
• Main Authors: Paragas, Neal, Kulkarni, Ritwij, Werth, Max, Schmidt-Ott, Kai M, Forster, Catherine, Deng, Rong, Zhang, Qingyin, Singer, Eugenia, Klose, Alexander D, Shen, Tian Huai, Francis, Kevin P, Ray, Sunetra, Vijayakumar, Soundarapandian, Seward, Samuel, Bovino, Mary E, Xu, Katherine, Takabe, Yared, Amaral, Fábio E, Mohan, Sumit, Wax, Rebecca, Corbin, Kaitlyn, Sanna-Cherchi, Simone, Mori, Kiyoshi, Johnson, Lynne, Nickolas, Thomas, D'Agati, Vivette, Lin, Chyuan-Sheng, Qiu, Andong, Al-Awqati, Qais, Ratner, Adam J, Barasch, Jonathan
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.07.2014
• Subjects: Acid-Base Equilibrium; Acute-Phase Proteins - deficiency; Acute-Phase Proteins - genetics; Acute-Phase Proteins - urine; Animals; Bacterial infections; Biological control systems; Disease Models, Animal; Escherichia coli Infections - microbiology; Escherichia coli Infections - prevention & control; Escherichia coli Infections - urine; Female; Humans; Hydrogen-Ion Concentration; Iron - metabolism; Kidney Tubules, Collecting - metabolism; Kidney Tubules, Collecting - pathology; Lipocalin-2; Lipocalins - genetics; Lipocalins - urine; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Oncogene Proteins - deficiency; Oncogene Proteins - genetics; Oncogene Proteins - urine; Physiological research; Prevention; Proto-Oncogene Proteins - urine; Toll-Like Receptor 4 - metabolism; Urinary Tract Infections - microbiology; Urinary Tract Infections - prevention & control; Urinary Tract Infections - urine; Urologic diseases; Uropathogenic Escherichia coli
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI71630

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.