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Neutrophil gelatinase-associated lipocalin protects from ANCA-induced GN by inhibiting T(H)17 immunity

Item Type:Article
Title:Neutrophil gelatinase-associated lipocalin protects from ANCA-induced GN by inhibiting T(H)17 immunity
Creators Name:Schreiber, A. and Rousselle, A. and Klocke, J. and Bachmann, S. and Popovic, S. and Bontscho, J. and Schmidt-Ott, K.M. and Siffrin, V. and Jerke, U. and Ashraf, M.I. and Panzer, U. and Kettritz, R.
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 T(H)17 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 T(H)17 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 T(H)17 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 T(H)17 immunity.
Keywords:ANCA Glomerulonephritis, ngal, TH17, Neutrophil, Animals, Mice
Source:Journal of the American Society of Nephrology
ISSN:1046-6673
Publisher:American Society of Nephrology
Volume:31
Number:7
Page Range:1569-1584
Date:July 2020
Official Publication:https://doi.org/10.1681/ASN.2019090879
PubMed:View item in PubMed

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