CC Chemokine Ligand 18 in ANCA-Associated Crescentic GN

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 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 2/2 mice had significantly less infiltration of pathogenic mononuclear phagocytes. Furthermore, Ccr8 2/2 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.

Coming of Age—CC Chemokine Ligand 18 in ANCA-Associated Vasculitis

“…16,22,23 Thus, one of the principal uncertainties is whether CCL18 has a pathogenic role in inflammatory disease or conversely, is part of a negative feedback loop that damps down over exuberant inflammation. The second part of the study by Brix et al 3 provides important new data on this question not available elsewhere, and this is, perhaps, the most novel aspect of the study.…”

“…12,13 Although promising, none of these have yet led to the development of a robust biomarker; hence, there is interest in the different strategy by Stahl and colleagues. 3 Brix et al 3 optimized methods for extracting mRNA from paraffin-embedded renal biopsies before using array technology to analyze the genes expressed in renal biopsies from a representative group of 30 patients with ANCAassociated crescentic GN. Brix et al 3 identified just over 1300 gene transcripts that were robustly overexpressed, whereas 342 were downregulated in patients' biopsies compared with healthy control kidneys.…”

“…The need for new approaches provided the starting point for a study from the laboratory of Stahl and colleagues in this issue of JASN. 3 Brix et al 3 suggest that the CC chemokine ligand 18 (CCL18) contributes to the pathogenesis of ANCA-associated crescentic GN and that its serum concentration may be a clinically relevant marker of disease intensity.…”

“…3 Brix et al 3 optimized methods for extracting mRNA from paraffin-embedded renal biopsies before using array technology to analyze the genes expressed in renal biopsies from a representative group of 30 patients with ANCAassociated crescentic GN. Brix et al 3 identified just over 1300 gene transcripts that were robustly overexpressed, whereas 342 were downregulated in patients' biopsies compared with healthy control kidneys. Brix et al 3 then focused on chemokine genes, because they were among the most highly expressed and because of their known importance for renal injury by recruiting and activating specific leukocyte subsets.…”

“…Brix et al 3 identified just over 1300 gene transcripts that were robustly overexpressed, whereas 342 were downregulated in patients' biopsies compared with healthy control kidneys. Brix et al 3 then focused on chemokine genes, because they were among the most highly expressed and because of their known importance for renal injury by recruiting and activating specific leukocyte subsets. 14 Of the many chemokine genes that were upregulated in patients' biopsies, CCL18 was the most highly expressed of all, with approximately 100-fold higher levels than in normal kidneys.…”