Human beta-defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with CCR2.
Human beta-defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with CCR2.
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DOI：
10.4049/jimmunol.0903984
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发表时间：
2010-06-15
期刊：
影响因子：
--
通讯作者：
Hehlgans T
中科院分区：
文献类型：
--
作者：
Röhrl J;Yang D;Oppenheim JJ;Hehlgans T
β-防御素在免疫反应中起双重作用。它们的直接抗菌特性有助于对抗微生物入侵的局部先天免疫反应。此外，先前的研究揭示了某些β-防御素家族成员通过趋化因子受体CCR6对未成熟树突状细胞和CD45RO+ CD4+ T细胞进行化学吸引的能力。然而，由于β-防御素也会吸引不表达CCR6的巨噬细胞和单核细胞，因此人们一直在努力确定这些多肽的其他受体。在这项研究中，我们证明了人β-防御素（hBD）2和3及其小鼠同源物β-防御素4和14与CCR2相互作用的能力，CCR2是一种在单核细胞、巨噬细胞和中性粒细胞上表达的趋化因子受体。流式细胞术显示，这些融合到人IgG1 Fc区的β-防御素与ccr2转染的HEK293细胞结合。β-防御素融合蛋白还以剂量依赖的方式诱导转染的HEK293细胞、人外周血单核细胞和小鼠腹膜渗出细胞的ccr2特异性趋化。用CCL2/MCP-1 （CCR2的趋化因子配体）对人单核细胞进行预孵育，可消除β-防御素诱导的迁移。相反，用hBD2:Ig或hBD3:Ig预孵卵可抑制MCP-1诱导的迁移。ccr2缺失小鼠的腹膜渗出细胞无法向这些融合蛋白迁移。总之，本研究中使用的β-防御素作为趋化剂参与先天和适应性免疫反应。我们的数据表明，hBD2和hBD3及其小鼠同源物（β-防御素4和14）以依赖CCR6和ccr2的方式对广谱白细胞具有趋化作用。
β-defensins play a dual role during immune response. Their direct antimicrobial properties contribute to the local innate immune response by combating microbial invasions. Furthermore, previous studies revealed the capacity of certain β-defensin family members to chemoattract immature dendritic cells and CD45RO+ CD4+ T cells through chemokine receptor CCR6. However, because β-defensins also chemoattract macrophages and monocytes, which do not express CCR6, efforts have been made to identify other receptors for these polypeptides. In this study, we demonstrate the capacity of human β-defensin (hBD)2 and 3 and their mouse orthologs, β-defensin 4 and 14, to interact with CCR2, a chemokine receptor expressed on monocytes, macrophages, and neutrophils. These β-defensins, fused to the Fc region of human IgG1, showed binding to CCR2-transfected HEK293 cells, as revealed by flow cytometry. The β-defensin fusion proteins also induced CCR2-specific chemotaxis of transfected HEK293 cells, human peripheral blood monocytes, and mouse peritoneal exudate cells in a dose-dependent manner. Preincubation of human monocytes with CCL2/MCP-1, the chemokine ligand for CCR2, abolished migration induced by β-defensins. Conversely, pre-incubation with hBD2:Ig or hBD3:Ig inhibited MCP-1 induced migration. Peritoneal exudate cells from CCR2-deficient mice failed to migrate toward these fusion proteins. In conclusion, the β-defensins used in this study contribute to the innate and adaptive immune response in their role as chemoattractants. Our data indicate that hBD2 and hBD3, together with their mouse orthologs (β-defensin 4 and 14), are chemotactic for a broad spectrum of leukocytes in a CCR6- and CCR2-dependent manner.
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