Autocrine production of IFN-gamma by macrophages controls their recruitment to kidney and the development of glomerulonephritis in MRL/lpr mice.
Anti-DNA autoantibody production is a key factor in lupus erythematosus development; nonetheless, the link between glomerular anti-DNA autoantibody deposition and glomerulonephritis development is not understood. To study the inflammatory and destructive processes in kidney, we used IFN-gamma(+/-) MRL/lpr mice which produce high anti-DNA Ab levels but are protected from kidney disease. The results showed that defective macrophage recruitment to IFN-gamma(+/-) mouse kidney was not caused by decreased levels of monocyte chemoattractant protein-1, a chemokine that controls macrophage migration to MRL/lpr mouse kidney. To determine which IFN-gamma-producing cell type orchestrates the inflammation pathway in kidney, we transferred IFN-gamma(+/+) monocyte/macrophages or T cells to IFN-gamma(-/-) mice, which do not develop anti-DNA autoantibodies. The data demonstrate that IFN-gamma production by infiltrating macrophages, and not by T cells, is responsible for adhesion molecule up-regulation, macrophage accumulation, and inflammation in kidney, even in the absence of autoantibody deposits. Therefore, in addition to monocyte chemoattractant protein-1, macrophage-produced IFN-gamma controls macrophage migration to kidney; the degree of IFN-gamma production by macrophages also regulates glomerulonephritis development. Our findings establish the level of IFN-gamma secretion by macrophages as a link between anti-DNA autoantibody deposition and glomerulonephritis development, outline the pathway of the inflammatory process, and suggest potential treatment for disease even after autoantibody development.
Carvalho-Pinto
Carla E
CE
Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Cantoblanco, Madrid, Spain.
García
María I
MI
Mellado
Mario
M
Rodríguez-Frade
J Miguel
JM
Martín-Caballero
Juan
J
Flores
Juana
J
Martínez-A
Carlos
C
Balomenos
Dimitrios
D
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D019898:Autocrine Communication / Q000235:genetics / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D018932:Chemokine CCL2 / Q000096:biosynthesis; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006580:Genetic Carrier Screening; D005921:Glomerulonephritis / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007668:Kidney / Q000276:immunology* / Q000473:pathology; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D001323:Autoantibodies; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D007371:Interferon-gamma