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Autocrine Production of IFN- by Macrophages Controls Their Recruitment to Kidney and the Development of Glomerulonephritis in MRL/lpr Mice¹

Carla E. Carvalho-Pinto^*, María I. García^*, Mario Mellado^*, J. Miguel Rodríguez-Frade^*, Juan Martín-Caballero^*, Juana Flores, Carlos Martínez-A^* and Dimitrios Balomenos^2,*

^* Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Cantoblanco, Madrid, Spain; and Departamento de Patología Animal II, Facultad de Veterinaria, Universidad de Complutense, Madrid, Spain

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-^+/- 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-^+/- 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--producing cell type orchestrates the inflammation pathway in kidney, we transferred IFN-^+/+ monocyte/macrophages or T cells to IFN-^-/- mice, which do not develop anti-DNA autoantibodies. The data demonstrate that IFN- 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- controls macrophage migration to kidney; the degree of IFN- production by macrophages also regulates glomerulonephritis development. Our findings establish the level of IFN- 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.

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