Leukocyte-derived MMP9 is crucial for the recruitment of proinflammatory macrophages in experimental glomerulonephritis

• Published in: Kidney international Vol. 83; no. 5; pp. 865 - 877
• Main Authors: Kluger, Malte A, Zahner, Gunther, Paust, Hans-Joachim, Schaper, Melanie, Magnus, Tim, Panzer, Ulf, Stahl, Rolf A K
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2013; Elsevier Limited
• Subjects: Animals; Bone Marrow Transplantation; Cells, Cultured; Chemokines - metabolism; Chemotaxis; cytokines; Disease Models, Animal; Disease Progression; extracellular matrix; glomerular disease; Glomerulonephritis - enzymology; Glomerulonephritis - immunology; Glomerulonephritis - pathology; Glomerulonephritis - prevention & control; immunology and pathology; inflammation; Inflammation Mediators - metabolism; Leukocytes - enzymology; Leukocytes - immunology; Macrophages, Peritoneal - enzymology; Macrophages, Peritoneal - immunology; Male; Matrix Metalloproteinase 9 - deficiency; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Nephrons - enzymology; Nephrons - immunology; Nephrons - pathology; Phenotype; Time Factors; immunology and pathology; cytokines; glomerular disease; inflammation; extracellular matrix
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/ki.2012.483

Matrix metalloproteinase 9 (MMP9) is a conditionally expressed enzyme and is upregulated in glomerulonephritis. Its function in these diseases, however, remains to be fully elucidated. The induction of nephrotoxic serum nephritis (NTN) in wild-type mice resulted in an upregulation of MMP9, followed by leukocyte infiltration, albuminuria, and subsequent renal failure. MMP9 deficiency ameliorated the course of NTN as indicated by reduced histological injury and reduced infiltration of proinflammatory macrophages. The chemotaxis of MMP9-deficient macrophages in vitro was impaired. Intrarenal macrophages isolated from the kidneys of nephritic MMP9 knockout mice still displayed the typical features of a proinflammatory phenotype and were indistinguishable from wild type–derived cells. Bone marrow transplantation restored renal tissue injury and macrophage recruitment when wild type–derived donor cells were transplanted onto MMP9-deficient mice prior to the induction of NTN. Thus, leukocyte-derived MMP9 mediates the recruitment of proinflammatory macrophages into kidneys during experimental crescentic glomerulonephritis.