An adapted passive model of anti-MPO dependent crescentic glomerulonephritis reveals matrix dysregulation and is amenable to modulation by CXCR4 inhibition.
Fiche publication
Date publication
janvier 2022
Journal
Matrix biology : journal of the International Society for Matrix Biology
Auteurs
Membres identifiés du Cancéropôle Est :
Dr OREND Gertraud
Tous les auteurs :
Faycal CA, Oszwald A, Feilen T, Contreras MJC, Schilling O, Loustau T, Steinbach F, Schachner H, Langer B, Heeringa P, Rees AJ, Orend G, Kain R
Lien Pubmed
Résumé
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.
Mots clés
AAV, AGC, automatic gain control, AU, arbitrary unit, Anti-neutrophil cytoplasmic antibody associated vasculitis, CFA, complete Freund's adjuvant, CXCL1/2/12, chemokine (C-X-C motif) ligand 1/2/12, CXCR4, CXCR4, C-X-C motif chemokine receptor 4, Col, collagen, DIA, data independent acquisition, DN, diabetic nephropathy, FN, fibronectin, FNGN, focal necrotizing glomerulonephritis, FSGS, focal segmental glomerulosclerosis, FoxP3, forkhead box P3, GBM, glomerular basement membrane, GPF, gas phase fractionation, ICAM1, intercellular Adhesion Molecule 1, IHC, indirect immunohistochemistry, IIF, indirect immunofluorescence, IL1β, interleukin 1 beta, IL6, interleukin 6, LC-MS/MS, Liquid Chromatography with tandem mass spectrometry, LD, living donor, LPS, lipopolysaccharide, MCD, minimal change disease, MMP9, matrix metallopeptidase 9, MPO, Myeloperoxidase, NE, neutrophil elastase, PCA, principal component analysis, PDS, pathway dysregulation scores, TGFβ, transforming growth factor beta, TNC, tenascin-C, VCAM1, vascular cell adhesion molecule 1, VCAN, versican, mIgG, murine IgG, matrisome, αSMA, smooth muscle alpha-actin
Référence
Matrix Biol. 2022 Jan 12;: