CC Chemokine Ligand 18 in ANCA-Associated Crescentic GN

ANCA-associated vasculitis is the most frequent cause of crescentic GN. To define new molecular and/or cellular biomarkers of this disease in the kidney, we performed microarray analyses of renal biopsy samples from patients with ANCA-associated crescentic GN. Expression profiles were correlated wit...

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Bibliographic Details
Published in:Journal of the American Society of Nephrology 2015-09, Vol.26 (9), p.2105-2117
Main Authors: Brix, Silke R, Stege, Gesa, Disteldorf, Erik, Hoxha, Elion, Krebs, Christian, Krohn, Sonja, Otto, Benjamin, Klätschke, Kristin, Herden, Elisabeth, Heymann, Felix, Lira, Sergio A, Tacke, Frank, Wolf, Gunter, Busch, Martin, Jabs, Wolfram J, Özcan, Fedai, Keller, Frieder, Beige, Joachim, Wagner, Karl, Helmchen, Udo, Noriega, Mercedes, Wiech, Thorsten, Panzer, Ulf, Stahl, Rolf A K
Format: Article
Language:English
Subjects:
Aged
Animals
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - complications
Basic Research
Biomarkers - blood
Chemokine CCL8 - genetics
Chemokine CCL8 - metabolism
Chemokines, CC - analysis
Chemokines, CC - blood
Dendritic Cells - chemistry
Female
Glomerulonephritis - etiology
Glomerulonephritis - metabolism
Glomerulonephritis - pathology
Glomerulonephritis - physiopathology
Humans
Macrophages - chemistry
Male
Mice
Middle Aged
Prospective Studies
Protein Array Analysis
Receptors, CCR8 - genetics
Receptors, CCR8 - metabolism
Up-Regulation
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Summary:ANCA-associated vasculitis is the most frequent cause of crescentic GN. To define new molecular and/or cellular biomarkers of this disease in the kidney, we performed microarray analyses of renal biopsy samples from patients with ANCA-associated crescentic GN. Expression profiles were correlated with clinical data in a prospective study of patients with renal ANCA disease. CC chemokine ligand 18 (CCL18), acting through CC chemokine receptor 8 (CCR8) on mononuclear cells, was identified as the most upregulated chemotactic cytokine in patients with newly diagnosed ANCA-associated crescentic GN. Macrophages and myeloid dendritic cells in the kidney were detected as CCL18-producing cells. The density of CCL18(+) cells correlated with crescent formation, interstitial inflammation, and impairment of renal function. CCL18 protein levels were higher in sera of patients with renal ANCA disease compared with those in sera of patients with other forms of crescentic GN. CCL18 serum levels were higher in patients who suffered from ANCA-associated renal relapses compared with those in patients who remained in remission. Using a murine model of crescentic GN, we explored the effects of the CCL18 murine functional analog CCL8 and its receptor CCR8 on kidney function and morphology. Compared with wild-type mice, Ccr8(-/-) mice had significantly less infiltration of pathogenic mononuclear phagocytes. Furthermore, Ccr8(-/-) mice maintained renal function better and had reduced renal tissue injury. In summary, our data indicate that CCL18 drives renal inflammation through CCR8-expressing cells and could serve as a biomarker for disease activity and renal relapse in ANCA-associated crescentic GN.
ISSN:1046-6673
1533-3450
DOI:10.1681/ASN.2014040407