An adapted passive model of anti-MPO dependent crescentic glomerulonephritis reveals matrix dysregulation and is amenable to modulation by CXCR4 inhibition.

Autor: Fayçal CA; INSERM U1109, The Tumor Microenvironment Laboratory, Strasbourg, France; Université Strasbourg, Hopital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France; These authors (CAF and AO) contributed equally to this work., Oszwald A; Department of Pathology, Medical University of Vienna, Vienna, Austria; These authors (CAF and AO) contributed equally to this work., Feilen T; Institute of Surgical Pathology, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Schänzlestraße 1, 79104 Freiburg, Germany., Cosenza-Contreras M; Institute of Surgical Pathology, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Schänzlestraße 1, 79104 Freiburg, Germany., Schilling O; Institute of Surgical Pathology, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK) and Cancer Research Center (DKFZ), Hugstetter Straße 55, 79106 Freiburg, Germany., Loustau T; INSERM U1109, The Tumor Microenvironment Laboratory, Strasbourg, France; Université Strasbourg, Hopital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France., Steinbach F; INSERM U1109, The Tumor Microenvironment Laboratory, Strasbourg, France; Université Strasbourg, Hopital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France., Schachner H; Department of Pathology, Medical University of Vienna, Vienna, Austria., Langer B; Department of Pathology, Medical University of Vienna, Vienna, Austria., Heeringa P; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Rees AJ; Department of Pathology, Medical University of Vienna, Vienna, Austria., Orend G; INSERM U1109, The Tumor Microenvironment Laboratory, Strasbourg, France; Université Strasbourg, Hopital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France. Electronic address: gertraud.orend@inserm.fr., Kain R; Department of Pathology, Medical University of Vienna, Vienna, Austria. Electronic address: renate.kain@meduniwein.ac.at.
Jazyk: angličtina
Zdroj: Matrix biology : journal of the International Society for Matrix Biology [Matrix Biol] 2022 Feb; Vol. 106, pp. 12-33. Date of Electronic Publication: 2022 Jan 13.
DOI: 10.1016/j.matbio.2022.01.001
Abstrakt: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are severe inflammatory disorders that often involve focal necrotizing glomerulonephritis (FNGN) and consequent glomerular scarring, interstitial fibrosis, and chronic kidney disease. Robust murine models of scarring in FNGN that may help to further our understanding of deleterious processes are still lacking. Here, we present a murine model of severe FNGN based on combined administration of antibodies against the glomerular basement membrane (GBM) and myeloperoxidase (MPO), and bacterial lipopolysaccharides (LPS), that recapitulates acute injury and was adapted to investigate subsequent glomerular and interstitial scarring. Hematuria without involvement of other organs occurs consistently and rapidly, glomerular necrosis and crescent formation are evident at 12 days, and consequent glomerular and interstitial scarring at 29 days after initial treatment. Using mass-spectrometric proteome analysis, we provide a detailed overview of matrisomal and cellular changes in our model. We observed increased expression of the matrisome including collagens, fibronectin, tenascin-C, in accordance with human AAV as deduced from analysis of gene expression microarrays and tissue staining. Moreover, we observed tissue infiltration by neutrophils, macrophages, T cells and myofibroblasts upon injury. Experimental inhibition of CXCR4 using AMD3100 led to a sustained histological presence of fibrin extravasate, reduced chemokine expression and leukocyte activation, but did not markedly affect ECM composition. Altogether, we demonstrate an adapted FNGN model that enables the study of matrisomal changes both in disease and upon intervention, as exemplified via CXCR4 inhibition.
Competing Interests: Declaration of competing interests The authors declare no competing financial interests.
(Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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