Ito Ayaka, Suganami Takayoshi, Yamauchi Akira, Degawa-Yamauchi Mikako, Tanaka Miyako, Kouyama Ryuji, Kobayashi Yuko, Nitta Nao, Yasuda Kazuki, Hirata Yukio, Kuziel William A, Takeya Motohiro, Kanegasaki Shiro, Kamei Yasutomi, Ogawa Yoshihiro
Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Tokyo 113-8510, Japan.
J Biol Chem. 2008 Dec 19;283(51):35715-23. doi: 10.1074/jbc.M804220200. Epub 2008 Oct 30.
The MCP-1 (monocyte chemoattractant protein-1)/CCR2 (CC motif chemokine receptor-2) pathway may play a role in macrophage infiltration into obese adipose tissue. Here we investigated the role of CCR2 in the recruitment of bone marrow-derived macrophages into obese adipose tissue in vitro and in vivo. Using the TAXIScan device, which can measure quantitatively the directionality and velocity of cell migration at time lapse intervals in vitro, we demonstrated that bone marrow cells (BMCs) from wild type mice migrate directly toward MCP-1 or culture medium conditioned by adipose tissue explants of genetically obese ob/ob mice, which are efficiently suppressed by pharmacological blockade of CCR2 signaling. The number of F4/80-positive macrophages was reduced in the adipose tissue from high fat diet-fed obese KKAy or ob/ob mice treated with a CCR2 antagonist propagermanium relative to vehicle-treated groups. We also found that the number of macrophages is reduced in the adipose tissue from ob/ob mice reconstituted with CCR2(-/-) BMCs (ob/ob + CCR2(-/-) BMCs) relative to those with CCR2+/+ BMCs (ob/ob + CCR2+/+ BMCs). Expression of mRNAs for CD11c and TLR4 (Toll-like receptor 4) markers of proinflammatory M1 macrophages was also decreased in the adipose tissue from ob/ob + CCR2(-/-) BMCs relative to ob/ob + CCR2+/+ BMCs, whereas mannose receptor and CD163, markers of anti-inflammatory M2 macrophages, were unchanged. This study provides in vivo and in vitro evidence that CCR2 in bone marrow cells plays an important role in the recruitment of macrophages into obese adipose tissue.
单核细胞趋化蛋白-1（MCP-1）/CC基序趋化因子受体2（CCR2）信号通路可能在巨噬细胞浸润肥胖脂肪组织过程中发挥作用。在此，我们研究了CCR2在体外和体内骨髓来源巨噬细胞募集至肥胖脂肪组织中的作用。使用TAXIScan设备，其可在体外以时间间隔定量测量细胞迁移的方向性和速度，我们证明野生型小鼠的骨髓细胞（BMCs）直接向MCP-1或由遗传性肥胖ob/ob小鼠的脂肪组织外植体条件培养基迁移，而CCR2信号的药理学阻断可有效抑制这种迁移。相对于载体处理组，用CCR2拮抗剂脯氨酸锗处理的高脂饮食喂养的肥胖KKAy或ob/ob小鼠的脂肪组织中，F4/80阳性巨噬细胞数量减少。我们还发现，相对于用CCR2+/+ BMCs重建的ob/ob小鼠（ob/ob + CCR2+/+ BMCs），用CCR2(-/-) BMCs重建的ob/ob小鼠（ob/ob + CCR2(-/-) BMCs）的脂肪组织中巨噬细胞数量减少。相对于ob/ob + CCR2+/+ BMCs，ob/ob + CCR2(-/-) BMCs的脂肪组织中促炎性M1巨噬细胞的CD11c和Toll样受体4（TLR4）标志物的mRNA表达也降低，而抗炎性M2巨噬细胞的标志物甘露糖受体和CD163则未改变。本研究提供了体内和体外证据，表明骨髓细胞中的CCR2在巨噬细胞募集至肥胖脂肪组织中起重要作用。
