CC chemokine ligand 18 in ANCA-associated crescentic GN

Silke R. Brix, Gesa Stege, Erik Disteldorf, Elion Hoxha, Christian Krebs, Sonja Krohn, Benjamin Otto, Kristin Klätschke, Elisabeth Herden, Felix Heymann, Sergio A. Lira, Frank Tacke, Gunter Wolf, Martin Busch, Wolfram J. Jabs, Fedai Özcan, Frieder Keller, Joachim Beige, Karl Wagner, Udo HelmchenMercedes Noriega, Thorsten Wiech, Ulf Panzer, Rolf A.K. Stahl

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

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 correlatedwith 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 serumlevels 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.

Original languageEnglish
Pages (from-to)2105-2117
Number of pages13
JournalJournal of the American Society of Nephrology : JASN
Volume26
Issue number9
DOIs
StatePublished - 1 Sep 2015

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