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Pivotal role of Ccr1 in murine lupus nephritis

Bignon, Alexandre and Gaudin, Françoise and Hémon, Patrice and Tharinger, Hugo and Loetscher, Pius and Peuchmaur, Michel and Berrebi, Dominique and Balabanian, Karl (2013) Pivotal role of Ccr1 in murine lupus nephritis. Journal of Immunology.

Abstract

Systemic Lupus Erythematosus is a chronic, inflammatory autoimmune disease that affects multiple organs including the kidney. Mononuclear cell infiltration in both glomerular and tubulointerstitial compartments characterizes human and experimental lupus nephritis and is associated with a progressive loss of renal function. Molecular recruitment mechanisms into chronically inflamed kidneys have not been fully characterized especially in the lupus-prone New Zealand Black/New Zealand White (NZB/W) mouse model. By combining pharmacologic and functional approaches, we uncover a previously unappreciated role for the chemokine receptor Ccr1 in renal infiltration of myeloid and T cells in nephritis NZB/W mice. We revealed a functional expression of Ccr1 on peripheral T cells, macrophages and neutrophils from NZB/W mice. Acute treatment of nephritis NZB/W mice with the orally available Ccr1 antagonist BL5923 reduced kidney recruitment of myeloid and T cells, while sparing B cells. Late onset BL5923-based treatment delayed proteinuria and death in nephritis mice. This is likely related to the beneficial effect of Ccr1 blockade on interstitial infiltration of T cells and macrophages as well as on tubulointerstitial and glomerular injuries. In contrast, systemic and renal humoral autoimmunity was unaffected in BL5923-treated mice. Altogether, these findings highlight a pivotal role for Ccr1 in recruiting T and myeloid cells to inflamed kidneys of NZB/W mice and that such activity contributes to the progression of renal injury.

Item Type: Article
Keywords: chemokine, chemokine receptor antagonist CCR1 antagonist lupus nephritis
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/9139

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