Inhibition of CXCL16 attenuates inflammatory and progressive phases of anti-glomerular basement membrane antibody-associated glomerulonephritis

Chemokines recruit and activate leukocytes during inflammation. CXCL16 is a recently discovered chemokine that is expressed as a transmembrane protein that is cleaved to form the active, soluble chemokine. We analyzed the role of CXCL16 in the development of inflammation and in the progression of the anti-glomerular basement membrane (GBM) antibody-induced experimental glomerulonephritis in Wistar-Kyoto rats. CXCL16 was expressed in glomerular endothelial cells and mediated adhesion of macrophages expressing CXCL16 and its cognate receptor, CXCR6. Glomerular infiltrates displayed a strong migratory response to soluble CXCL16. Soluble CXCL16 and its receptor CXCR6 were induced in nephritic glomeruli throughout the disease, and CXCL16 expression correlated with the up-regulation of ADAM10, suggesting that this disintegrin and metalloproteinase mediates the chemokine activity of CXCL16. Blocking CXCL16 in the acute inflammatory phase or progressive phase of established glomerulonephritis significantly attenuated monocyte/macrophage infiltration and glomerular injury; proteinuria also improved. We conclude that CXCL16/CXCR6 plays a critical role in stimulating leukocyte influx, which causes glomerular damage during anti-GBM glomerulonephritis. Blocking CXCL16 actions limits the progression of anti-GBM glomerulonephritis even when the disease is established.