Proliferative lesions and metalloproteinase activity in murine lupus nephritis mediated by type I interferons and macrophages.
Glomerulonephritis is a major cause of morbidity in patients with systemic lupus erythematosus. Although substantial progress has been made in the identification of pathogenic triggers that result in autoantibody production, little is known about the pathogenesis of aggressive proliferative processes that lead directly to irreversible glomerular damage and compromise of renal function. In this study, we describe a model of polyinosinic: polycytidylic acid-accelerated lupus nephritis in NZB/W mice that is characterized by severe glomerular proliferative lesions with de novo crescent formation, findings that are linked with decreased survival and adverse outcomes in lupus. Proliferative glomerulonephritis was associated with infiltrating kidney macrophages and renal expression of IFN-inducible genes, matrix metalloproteinases (MMPs), and growth factors. Crescent formation and renal MMP and growth factor expression were dependent on renal macrophages that expressed Il10, MMPs, osteopontin, and growth factors, including Pdgfc and Hbegf. Infiltrating macrophages and renal MMP expression were induced by type I IFN. These findings reveal a role for type I IFNs and alternatively activated macrophages in aggressive proliferative lesions of lupus nephritis.
Arthritis and Tissue Degeneration Program, Department of Medicine, Hospital for Special Surgery, New York, NY 10021, USA.
Antigoni
A
Triantafyllopoulou
Claus-Werner
CW
Franzke
Surya V
SV
Seshan
Giorgio
G
Perino
George D
GD
Kalliolias
Meera
M
Ramanujam
Nico
N
van Rooijen
Anne
A
Davidson
Lionel B
LB
Ivashkiv
D000818:Animals; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D066257:Heparin-binding EGF-like Growth Factor; D015151:Immunoblotting; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism* / Q000633:toxicity; D016753:Interleukin-10 / Q000378:metabolism; D008181:Lupus Nephritis / Q000139:chemically induced* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology*; D008222:Lymphokines / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D045726:Metalloproteases / Q000378:metabolism*; D051379:Mice; D008814:Mice, Inbred NZB; D053495:Osteopontin / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011070:Poly I-C / Q000378:metabolism* / Q000633:toxicity; D011507:Proteinuria / Q000139:chemically induced*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric
C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D007370:Interferon Type I; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; C411423:platelet-derived growth factor C; D053495:Osteopontin; D016753:Interleukin-10; D045726:Metalloproteases; D011070:Poly I-C