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Basic Research
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Neutrophil Gelatinase–Associated Lipocalin Protects from ANCA-Induced GN by Inhibiting TH17 Immunity

Adrian Schreiber, Anthony Rousselle, Jan Klocke, Sebastian Bachmann, Suncica Popovic, Julia Bontscho, Kai M. Schmidt-Ott, Volker Siffrin, Uwe Jerke, Muhammad Imtiaz Ashraf, Ulf Panzer and Ralph Kettritz
JASN July 2020, 31 (7) 1569-1584; DOI: https://doi.org/10.1681/ASN.2019090879
Adrian Schreiber
1Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité – Berlin University of Medicine, Corporate Member of Free University of Berlin, Humboldt University of Berlin, Berlin Institute of Health, Berlin, Germany
2Nephrology and Medical Intensive Care Medicine, Charité – Berlin University of Medicine, Berlin, Germany
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Anthony Rousselle
1Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité – Berlin University of Medicine, Corporate Member of Free University of Berlin, Humboldt University of Berlin, Berlin Institute of Health, Berlin, Germany
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Jan Klocke
2Nephrology and Medical Intensive Care Medicine, Charité – Berlin University of Medicine, Berlin, Germany
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Sebastian Bachmann
3Institute of Vegetative Anatomy, Charité – Berlin University of Medicine, Berlin, Germany
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Suncica Popovic
3Institute of Vegetative Anatomy, Charité – Berlin University of Medicine, Berlin, Germany
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Julia Bontscho
2Nephrology and Medical Intensive Care Medicine, Charité – Berlin University of Medicine, Berlin, Germany
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Kai M. Schmidt-Ott
2Nephrology and Medical Intensive Care Medicine, Charité – Berlin University of Medicine, Berlin, Germany
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Volker Siffrin
1Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité – Berlin University of Medicine, Corporate Member of Free University of Berlin, Humboldt University of Berlin, Berlin Institute of Health, Berlin, Germany
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Uwe Jerke
1Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité – Berlin University of Medicine, Corporate Member of Free University of Berlin, Humboldt University of Berlin, Berlin Institute of Health, Berlin, Germany
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Muhammad Imtiaz Ashraf
4Department of Surgery, Campus Charité Mitte I Campus Virchow Klinikum, Charité – Berlin University of Medicine, Berlin, Germany
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Ulf Panzer
5III. Medical Clinic, Division of Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Ralph Kettritz
1Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité – Berlin University of Medicine, Corporate Member of Free University of Berlin, Humboldt University of Berlin, Berlin Institute of Health, Berlin, Germany
2Nephrology and Medical Intensive Care Medicine, Charité – Berlin University of Medicine, Berlin, Germany
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Significance Statement

Neutrophil gelatinase–associated lipocalin (NGAL) is produced by injured renal cells and by neutrophils that are central to ANCA-associated vasculitis. The authors show that circulating and urinary NGAL is not only a marker for ANCA-induced necrotizing crescentic GN, but also that neutrophil NGAL is involved mechanistically in ANCA-associated vasculitis. They demonstrate that ANCA-activated neutrophils release NGAL, and that chimeric mice deficient in neutrophil-derived NGAL develop accelerated myeloperoxidase-ANCA–induced crescentic GN, with increased renal CD4+ T cells—particularly T helper 17 (TH17) cells—acting as mediators of the accelerated phenotype. They also demonstrated that iron siderophore–loaded NGAL suppresses TH17 polarization. Their findings indicate that bone marrow–derived NGAL, presumably from neutrophils, protects from ANCA-induced necrotizing and crescentic GN by downregulating TH17 immunity.

Abstract

Background Neutrophil gelatinase–associated lipocalin (NGAL) is a diagnostic marker of intrinsic kidney injury produced by damaged renal cells and by neutrophils. ANCA-associated vasculitis features necrotizing crescentic GN (NCGN), and ANCA-activated neutrophils contribute to NCGN. Whether NGAL plays a mechanistic role in ANCA-associated vasculitis is unknown.

Methods We measured NGAL in patients with ANCA-associated vasculitis and mice with anti-myeloperoxidase (anti-MPO) antibody–induced NCGN. We compared kidney histology, neutrophil functions, T cell proliferation and polarization, renal infiltrating cells, and cytokines in wild-type and NGAL-deficient chimeric mice with anti-MPO antibody–induced NCGN. To assess the role of TH17 immunity, we transplanted irradiated MPO-immunized MPO-deficient mice with bone marrow from either wild-type or NGAL-deficient mice; we also transplanted irradiated MPO-immunized MPO/IL-17A double-deficient mice with bone marrow from either IL-17A–deficient or NGAL/IL-17A double-deficient mice.

Results Mice and patients with active ANCA-associated vasculitis demonstrated strongly increased serum and urinary NGAL levels. ANCA-stimulated neutrophils released NGAL. Mice with NGAL-deficient bone marrow developed worsened MPO-ANCA–induced NCGN. Intrinsic neutrophil functions were similar in NGAL-deficient and wild-type neutrophils, whereas T cell immunity was increased in chimeric mice with NGAL-deficient neutrophils with more renal infiltrating TH17 cells. NGAL-expressing neutrophils and CD3+ T cells were in close proximity in kidney and spleen. CD4+ T cells showed no intrinsic difference in proliferation and polarization in vitro, whereas iron siderophore–loaded NGAL suppressed TH17 polarization. We found significantly attenuated NCGN in IL-17A–deficient chimeras compared with MPO-deficient mice receiving wild-type bone marrow, as well as in NGAL/IL-17A–deficient chimeras compared with NGAL-deficient chimeras.

Conclusions Our findings support that bone marrow–derived, presumably neutrophil, NGAL protects from ANCA-induced NCGN by downregulating TH17 immunity.

  • ANCA glomerulonephritis
  • ngal
  • TH17
  • neutrophil
  • Copyright © 2020 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 31 (7)
Journal of the American Society of Nephrology
Vol. 31, Issue 7
July 2020
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Neutrophil Gelatinase–Associated Lipocalin Protects from ANCA-Induced GN by Inhibiting TH17 Immunity
Adrian Schreiber, Anthony Rousselle, Jan Klocke, Sebastian Bachmann, Suncica Popovic, Julia Bontscho, Kai M. Schmidt-Ott, Volker Siffrin, Uwe Jerke, Muhammad Imtiaz Ashraf, Ulf Panzer, Ralph Kettritz
JASN Jul 2020, 31 (7) 1569-1584; DOI: 10.1681/ASN.2019090879

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Neutrophil Gelatinase–Associated Lipocalin Protects from ANCA-Induced GN by Inhibiting TH17 Immunity
Adrian Schreiber, Anthony Rousselle, Jan Klocke, Sebastian Bachmann, Suncica Popovic, Julia Bontscho, Kai M. Schmidt-Ott, Volker Siffrin, Uwe Jerke, Muhammad Imtiaz Ashraf, Ulf Panzer, Ralph Kettritz
JASN Jul 2020, 31 (7) 1569-1584; DOI: 10.1681/ASN.2019090879
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