title: Tamm-Horsfall Protein Regulates Granulopoiesis and Systemic Neutrophil Homeostasis.
abstract: Tamm-Horsfall protein (THP) is a glycoprotein uniquely expressed in the kidney. We recently showed an important role for THP in mediating tubular cross-talk in the outer medulla and in suppressing neutrophil infiltration after kidney injury. However, it remains unclear whether THP has a broader role in neutrophil homeostasis. In this study, we show that THP deficiency in mice increases the number of neutrophils, not only in the kidney but also in the circulation and in the liver, through enhanced granulopoiesis in the bone marrow. Using multiplex ELISA, we identified IL-17 as a key granulopoietic cytokine specifically upregulated in the kidneys but not in the liver of THP(-/-) mice. Indeed, neutralization of IL-17 in THP(-/-) mice completely reversed the systemic neutrophilia. Furthermore, IL-23 was also elevated in THP(-/-) kidneys. We performed real-time PCR on laser microdissected tubular segments and FACS-sorted renal immune cells and identified the S3 proximal segments, but not renal macrophages, as a major source of increased IL-23 synthesis. In conclusion, we show that THP deficiency stimulates proximal epithelial activation of the IL-23/IL-17 axis and systemic neutrophilia. Our findings provide evidence that the kidney epithelium in the outer medulla can regulate granulopoiesis. When this novel function is added to its known role in erythropoiesis, the kidney emerges as an important regulator of the hematopoietic system.
authors.affiliation: Divisions of Nephrology and.
authors.forename: Radmila
authors.initials: R
authors.lastname: Micanovic
authors.affiliation: Hematology, Microbiology, and Immunology, Indiana University School of Medicine, Indianapolis, Indiana;
authors.forename: Brahmananda R
authors.initials: BR
authors.lastname: Chitteti
authors.affiliation: Divisions of Nephrology and.
authors.forename: Pierre C
authors.initials: PC
authors.lastname: Dagher
authors.affiliation: Hematology, Microbiology, and Immunology, Indiana University School of Medicine, Indianapolis, Indiana;
authors.forename: Edward F
authors.initials: EF
authors.lastname: Srour
authors.affiliation: Divisions of Nephrology and.
authors.forename: Shehnaz
authors.initials: S
authors.lastname: Khan
authors.affiliation: Divisions of Nephrology and.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hato
authors.affiliation: Divisions of Nephrology and.
authors.forename: Allison
authors.initials: A
authors.lastname: Lyle
authors.affiliation: Divisions of Nephrology and Hematology, Microbiology, and Immunology, Indiana University School of Medicine, Indianapolis, Indiana; Department of Biostatistics, Indiana University Schools of Medicine and Public Health, Indianapolis, Indiana; Departments of Urology and Pathology, New York University School of Medicine and Veterans Affairs New York Harbor Healthcare System Manhattan Campus, New York, New York; and Roudebush Indianapolis Veterans Affairs Medical Center, Indianapolis, Indiana.
authors.forename: Yan
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Departments of Urology and Pathology, New York University School of Medicine and Veterans Affairs New York Harbor Healthcare System Manhattan Campus, New York, New York; and.
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
authors.affiliation: Divisions of Nephrology and Roudebush Indianapolis Veterans Affairs Medical Center, Indianapolis, Indiana telachka@iu.edu.
authors.forename: Tarek M
authors.initials: TM
authors.lastname: El-Achkar
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000502:physiology; D006098:Granulocytes; D006410:Hematopoiesis; D006706:Homeostasis; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils; D058949:Uromodulin / Q000172:deficiency* / Q000235:genetics
chemical_list: D020381:Interleukin-17; D053759:Interleukin-23; D058949:Uromodulin
keywords: chemokine; cytokines; immunology; pathology; renal injury