The atypical chemokine receptor ACKR4 facilitates dendritic cell migration during inflammation by scavenging CCL19 (CCR3P.205)

Abstract The migration of dendritic cells from tissues to draining lymph nodes is a critical step in the induction of peripheral tolerance and the initiation of adaptive immune responses. This is dependent on CCR7 expression by dendritic cells. In response to the chemokine CCL21, CCR7 directs dendritic cells into lymphatic vessels in the tissue, and permits their transit from the subcapsular sinus into the lymph node parenchyma. The CCR7 ligands CCL19 and CCL21 also bind ACKR4, an atypical chemokine receptor expressed by keratinocytes in the skin and lymphatic endothelial cells lining the subcapsular sinus. In mice, ACKR4 controls interfollicular CCL21 gradients, and enhances dendritic cell entry into the lymph node parenchyma from the subcapsular sinus. Here we report that Ackr4 deficiency disrupts CCR7-dependent dendritic cell arrival at skin-draining lymph nodes during cutaneous inflammation. We show that this, at least in part, is due to the defective departure of dendritic cells from inflamed skin, and is accompanied by dysregulation of bioavailable CCL19 and CCL21 in the skin. Strikingly, genetic deletion of CCL19 completely rescues the defective inflammation-driven trafficking of dendritic cells caused by Ackr4 deficiency. Thus, by regulating CCL19, ACKR4 helps maintain CCR7-dependent dendritic cell departure from inflamed tissues.