Search

AMD3100 is approved for mobilizing hematopoietic stem cells to blood for transplantation in cancer by blocking chemokine receptor CXCR4. It also mobilizes mature leukocytes to blood; however, there is conflicting published evidence regarding the source of mobilized neutrophils (bone marrow vs lung), and the source(s) of other mobilized leukocytes is unknown. Here we used surgical, pharmacologic and histologic approaches to address these questions in mice. AMD3100 10 mg/kg sq mobilized the same leukocyte subsets to blood in mice as in humans, and increased neutrophil and monocyte content in lung and lymph node, while reducing neutrophil, lymphocyte and monocyte content in bone marrow as well as T cell content in thymus. Direct intrathymic labeling showed that AMD3100 mobilized naïve CD4+ and CD8+ T cells to blood. In contrast, splenectomy and experiments with FTY720, which blocks T cell egress from lymph node, suggested that spleen and lymph node were not major sources of AMD3100-mobilized cells. Importantly, AMD3100 did not inhibit neutrophil trafficking to thioglycollate-inflamed peritoneum. These data provide evidence that CXCR4 is a selective compartmentalization factor for both bone marrow (lymphocyte, monocyte, neutrophil) and thymus (naïve T cells), but is not critical for homeostatic trafficking of leukocytes to uninflamed tissues or for innate immune responses to inflamed sites, a profile that is favorable for chronic administration of AMD3100 in patients.

Background—The chemokine receptor CCR6 and its ligand CCL20 are both expressed in human atheroma; however, their functional roles in atherogenesis remain undefined. Here, we addressed this question in the apolipoprotein E-deficient (ApoE-/-) mouse model of atherosclerosis. Methods and Results—Both Ccr6 and Ccl20 are expressed in atherosclerotic aorta from ApoE-/- mice. Atherosclerotic lesion area in the aorta in Ccr6-/-ApoE-/- mice was ~40% and ~30% smaller than in Ccr6+/+ApoE-/- mice at 16 and 24 weeks of age, respectively. In addition, lesions of Ccr6-/-ApoE-/- mice had 44% less macrophage content compared to Ccr6+/+ApoE-/- mice. Since monocytes are the source of lesional macrophages, we tested whether monocytes express Ccr6 and the effect of Ccr6 deletion on monocyte function. We found that Ccr6 was expressed on a subset of primary mouse monocytes and on the mouse monocyte/macrophage cell line RAW 264.7. The receptor was functional, as defined by Ccl20-induced chemotaxis of primary monocytes from wild type but not Ccr6-/- mice; moreover, Ccl20 induced monocytosis in ApoE-/- mice in vivo. Consistent with this, we observed 30% fewer monocytes in the circulating blood of Ccr6-/-ApoE-/- mice, mainly due to fewer CD11b+Ly6Chigh inflammatory monocytes. Conclusions—We conclude that Ccr6 promotes atherosclerosis in ApoE-deficient mice. This may be due in part to Ccr6 support of normal monocyte levels in blood in the model, as well as direct Ccr6-dependent monocyte migration.