title: α-Intercalated cells defend the urinary system from bacterial infection.
abstract: 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.
authors.forename: Neal
authors.initials: N
authors.lastname: Paragas
authors.forename: Ritwij
authors.initials: R
authors.lastname: Kulkarni
authors.forename: Max
authors.initials: M
authors.lastname: Werth
authors.forename: Kai M
authors.initials: KM
authors.lastname: Schmidt-Ott
authors.forename: Catherine
authors.initials: C
authors.lastname: Forster
authors.forename: Rong
authors.initials: R
authors.lastname: Deng
authors.forename: Qingyin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Eugenia
authors.initials: E
authors.lastname: Singer
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Klose
authors.forename: Tian Huai
authors.initials: TH
authors.lastname: Shen
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Francis
authors.forename: Sunetra
authors.initials: S
authors.lastname: Ray
authors.forename: Soundarapandian
authors.initials: S
authors.lastname: Vijayakumar
authors.forename: Samuel
authors.initials: S
authors.lastname: Seward
authors.forename: Mary E
authors.initials: ME
authors.lastname: Bovino
authors.forename: Katherine
authors.initials: K
authors.lastname: Xu
authors.forename: Yared
authors.initials: Y
authors.lastname: Takabe
authors.forename: Fábio E
authors.initials: FE
authors.lastname: Amaral
authors.forename: Sumit
authors.initials: S
authors.lastname: Mohan
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wax
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Corbin
authors.forename: Simone
authors.initials: S
authors.lastname: Sanna-Cherchi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mori
authors.forename: Lynne
authors.initials: L
authors.lastname: Johnson
authors.forename: Thomas
authors.initials: T
authors.lastname: Nickolas
authors.forename: Vivette
authors.initials: V
authors.lastname: D'Agati
authors.forename: Chyuan-Sheng
authors.initials: CS
authors.lastname: Lin
authors.forename: Andong
authors.initials: A
authors.lastname: Qiu
authors.forename: Qais
authors.initials: Q
authors.lastname: Al-Awqati
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Ratner
authors.forename: Jonathan
authors.initials: J
authors.lastname: Barasch
mesh_terms: D000136:Acid-Base Equilibrium; D000209:Acute-Phase Proteins / Q000172:deficiency / Q000235:genetics / Q000652:urine*; D000818:Animals; D004195:Disease Models, Animal; D004927:Escherichia coli Infections / Q000382:microbiology / Q000517:prevention & control* / Q000652:urine; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007501:Iron / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000378:metabolism* / Q000473:pathology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000652:urine*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000652:urine*; D011518:Proto-Oncogene Proteins / Q000652:urine*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014552:Urinary Tract Infections / Q000382:microbiology / Q000517:prevention & control* / Q000652:urine; D056689:Uropathogenic Escherichia coli
chemical_list: D000209:Acute-Phase Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C071332:Lcn2 protein, mouse; D007501:Iron