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Tamm-Horsfall Protein Regulates Granulopoiesis and Systemic Neutrophil Homeostasis

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Tamm-Horsfall Protein Regulates Granulopoiesis and Systemic Neutrophil Homeostasis BASIC RESEARCH www.jasn.org Tamm-Horsfall Protein Regulates Granulopoiesis and Systemic Neutrophil Homeostasis † † Radmila Micanovic,* Brahmananda R. Chitteti, Pierre C. Dagher,* Edward F. Srour, Shehnaz Khan,* Takashi Hato,* Allison Lyle,* Yan Tong, Xue-Ru Wu,§ and | Tarek M. El-Achkar* 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 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 2 2 2 2 upregulated in the kidneys but not in the liver of THP / mice. Indeed, neutralization of IL-17 in THP / 2 2 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 acti- vation 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. J Am Soc Nephrol 26: 2172–2182, 2015. doi: 10.1681/ASN.2014070664 Tamm-Horsfallprotein(THP,alsoknownas THP and inflammation.8,11–13 We recently provided Uromodulin) is a unique glycoprotein because it is challenging evidence supporting a role for THP in exclusively expressed in the kidney, in tubular cells of controlling neutrophil infiltration during kidney the thick ascending limbs (TALs).1–3 Within TAL injury,2,5,10,14 and promoting recovery.5,14 The pres- cells, THP is targeted predominantly to the apical ence of THP released from TALs inhibits the produc- membrane domain, cleaved proteolytically, and se- tion of cytokines and chemokines such as CXCL214 creted in the urine. However, basolateral release of in injured neighboring proximal tubules (PTs), THP in the interstitium and circulation is also ob- served.1,4,5 The association of THP with acute and chronic forms of renal disease, such as familial juvenile Received July 11, 2014. Accepted October 30, 2014. hyperuricemic nephropathy, AKI, and CKD, argues Published online ahead of print. Publication date available at for important regulatory functions of this glycoprotein www.jasn.org. 1,4,6–10 in the pathogenesis of kidney disease. Interest- Correspondence: Dr. Tarek M. El-Achkar, Division of Nephrology, ingly, interstitial deposits of THP are frequently asso- Indiana University School of Medicine, 950 W. Walnut Street, ciated with tubulointerstitial diseases, suggesting a R2 E224, Indianapolis, IN 46202. Email: [email protected] potential link between the interstitial presence of Copyright © 2015 by the American Society of Nephrology 2172 ISSN : 1046-6673/2609-2172 JAmSocNephrol26: 2172–2182, 2015 www.jasn.org BASIC RESEARCH suggesting that THP mediates a regulatory cross-talk between TALs and PTs serving to suppress inflammation and neutrophil infiltration.2 The expression of THP and its level in the circulation are significantly decreased in various forms of kidney disease.2,5,15,16 For example, the expression of THP is significantly reduced at the peak of AKI.5,17,18 Furthermore, several studies have con- firmed that advanced CKD is associated with decreased levels of THP in the urine and in the circulation,16,19,20 thereby creating a state of “relative THP deficiency.” Interestingly, in a murine knockout model, THP deficiency in a noninjured state was as- sociated with a systemic increase in proinflammatory cytokines and chemokines.21 Therefore, these observations prompted us to examine the role of THP in regulating inflammation not only in the kidney, but also systemically. The possibility that THP regulates systemic inflammation could explain the general- ized inflammatory phenotype and neutrophilia observed in “THP-deficient states,” such as what is reported with ad- vanced CKD.22–25 This study was designed to investigate the effect of THP deficiency on systemic neutrophil homeostasis. We hypoth- esized that THP deficiency causes systemic neutrophilia through the production of growth factors by the kidney that stimulate granulopoiesis. We show, for the first time, that THP deficiency causes systemic neutrophilia, which is de- pendent on the renal activation of the IL-23/IL-17 axis. Surprisingly, our results underscore the importance of the proximal renal tubular epithelium in regulating systemic neutrophil homeostasis. Our novel findings expand the cross-talk between the kidney and bone marrow beyond the regulation of erythropoiesis, to also include the regulation of granulopoiesis. RESULTS THP Deficiency Causes Renal and Systemic Neutrophilia Immunohistochemistry for GR1 (a commonly used marker for 2 2 neutrophils) in THP+/+ and THP / kidneys shows an increase 2 2 in the number of GR1+ cells in THP / kidneys (Figure 1). This 2 2 was verified by flow cytometry for neutrophils in the kidney Figure 1. Immunohistochemistry of GR1 in THP+/+ and THP / (Figure 2, A and B), in which neutrophils were defined as CD45+, kidney sections. (A–H) Representative images of sections (two sec- + + 26 tions/kidney, five kidneys per group) encompassing all areas within CD11b , Ly6G . It is important to note that Ly6G is part of +/+ 2/2 the GR1 antigen complex, and is also considered a specific the kidney from THP and THP mice. Arrows show GR1-stained cells in various areas within the kidney. (I) Quantitation of GR1+ cells marker for neutrophils.26,27 The increased number of neutro- in each renal zone. Bar graphs are means6SEM. Asterisks repre- phils was present not only in the kidney, but also in the liver of fi P, 2/2 sents statistical signi cance between the two strains ( 0.05). THP mice (Figure 2, C and D) and in the spleen (Supple- Original magnification, 360 objective. mental Figure 1). We subsequently analyzed peripheral blood 2 2 counts in THP+/+ and THP / mice, and demonstrated that THP deficiency is associated with a significant increase in cir- THP Deficiency Causes Enhanced Granulopoiesis in the culating neutrophil counts (Figure 2, E and F). Taken together, Bone Marrow these results suggest that THP deficiency causes not only renal To verify whether the generalized systemic neutrophilia in the but also systemic neutrophilia that extends to other organs periphery and within organs was due to increased granulo- such as the liver. poiesis in the bone marrow, we performed detailed analysis of J Am Soc Nephrol 26: 2172–2182, 2015 THP and Neutrophil Homeostasis 2173 BASIC RESEARCH www.jasn.org 2 2 Figure 2. Peripheral and organ neutrophil analysis in THP+/+ and THP / mice. (A–D) Flow cytometry analysis of neutrophils in the kidney (A and B) and liver (C and D) from both strains of mice. A and C show representative scatter plots of CD45+ cells in the kidney and liver, respectively, gated for CD11b and Ly6G. Quantitation of neutrophils (defined as CD45+,CD11b+, Ly6G+) in the kidney and 2 2 liver are shown in B and D, respectively (n=5 per group). Asterisks denote statistical significance between THP+/+ and THP / (P,0.05). 2 2 (E and F) Bar graphs are means6SEM of peripheral white blood cell count and its subtypes from THP+/+ and THP / mice (n=8 per group). E depicts cell concentration in blood, whereas F shows the percentage of each cell type within the total white blood cell count. 2 2 Asignificant increase in neutrophils is noted in THP / versus THP+/+ (*P,0.05). Neut, neutrophil; WBC, white blood cell count; NE, neutrophil; LY, lymphocyte; MO, monocyte; EO, eosinophil; BA, basophil. 2 2 bone marrow from THP+/+ and THP / mice using flow cy- number of differentiated neutrophils expressing Ly6G (Figure tometry as described28–30 and shown in Figure 3, Supplemental 3B). The increased neutrophil count in the bone marrow was Figure 2. Figure 3A shows a significant decrease in the marrow of also verified using an automated hematology analyzer (Supple- 2 2 THP / mice of two classes of granulocyte progenitor cells: mental Figure 3). Taken together, our data provide strong evidence common myeloid progenitors and granulocyte-macrophage of enhanced granulopoiesis (decreased progenitors in the marrow, progenitors. In parallel, there was a significant increase in the increased circulating differentiated cells), which explains the 2174 Journal of the American Society of Nephrology J Am Soc Nephrol 26: 2172–2182, 2015 www.jasn.org BASIC RESEARCH Figure 3. Bone marrow analysis by flow cytometry. (A and B) Quantitation of progenitor cells within bone marrow (A) and quantitation of bone 2 2 marrow cells with differentiation markers (B), as described in the Concise Methods, from THP+/+ and THP / mice (n=5 each group). The Mw/ 2 DC population shown is CD11b+ and Ly6G . The decrease in granulocyte progenitors and increase in neutrophils strongly support enhanced 2 2 granulopoiesis. (C) ELISA assay for G-CSF, performed on sera from THP+/+ and THP / mice (n=5 each group).
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