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(American Journal of Pathology. 2005;167:1207-1219.)
© 2005 American Society for Investigative Pathology

Conditional Ablation of Macrophages Halts Progression of Crescentic Glomerulonephritis

Jeremy S. Duffield^*, Peter G. Tipping, Tiina Kipari^*, Jean-François Cailhier^*, Spike Clay^*, Richard Lang, Joseph V. Bonventre and Jeremy Hughes^*

From the Medical Research Council Centre for Inflammation Research Medical School,^* University of Edinburgh, Edinburgh, United Kingdom; the Department of Medicine, Monash University, Clayton, Melbourne, Australia; the Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and the Division of Developmental Biology and Department of Ophthalmology, Children’s Hospital Research Foundation, University of Cincinnati, Cincinnati, Ohio

The presence of macrophages in inflamed glomeruli of rat kidney correlates with proliferation and apoptosis of resident glomerular mesangial cells. We assessed the contribution of inflammatory macrophages to progressive renal injury in murine crescentic glomerulonephritis (GN). Using a novel transgenic mouse (CD11b-DTR) in which tissue macrophages can be specifically and selectively ablated by minute injections of diphtheria toxin, we depleted renal inflammatory macrophages through days 15 and 20 of progressive crescentic GN. Macrophage depletion reduced the number of glomerular crescents, improved renal function, and reduced proteinuria. Morphometric analysis of renal tubules and interstitium revealed a marked attenuation of tubular injury that was associated with reduced proliferation and apoptosis of tubular cells. The population of interstitial myofibroblasts decreased after macrophage depletion and interstitial fibrosis also decreased. In the presence of macrophages, interstitial myofibroblasts exhibited increased levels of both proliferation and apoptosis, suggesting that macrophages act to support a population of renal myofibroblasts in a high turnover state and in matrix deposition. Finally, deletion of macrophages reduced CD4 T cells in the diseased kidney. This study demonstrates that macrophages are key effectors of disease progression in crescentic GN, acting to regulate parenchymal cell populations by modulating both cell proliferation and apoptosis.

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