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