Chemerin Contributes to Inflammation by Promoting Macrophage Adhesion to VCAM-1 and Fibronectin through Clustering of VLA-4 and VLA-5
Chemerin Contributes to Inflammation by Promoting Macrophage Adhesion to VCAM-1 and Fibronectin through Clustering of VLA-4 and VLA-5
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DOI：
10.4049/jimmunol.0902154
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发表时间：
2010-09-15
影响因子：
4.4
通讯作者：
Greaves, David R.
中科院分区：
文献类型：
--
作者：
Hart, Rosie;Greaves, David R.
趋化素是一种有效的巨噬细胞趋化蛋白。我们使用小鼠腹膜渗出细胞（PECs）进行粘附、流式细胞术和共聚焦显微镜分析，以验证趋化素也可以通过促进巨噬细胞粘附来促进炎症的假设。Chemerin在1分钟内刺激PECs与细胞外基质蛋白纤维连接蛋白和粘附分子VCAM-1的粘附，EC50分别为322 pM和196 pM。利用百日咳毒素和来自ChemR23（-/-）小鼠的PECs进行的实验表明，chemerin通过Gi蛋白偶联受体ChemR23刺激巨噬细胞的粘附。阻断针对整合素亚基的抗体显示，89%的趋化素刺激的纤维连接蛋白粘附依赖于整合素vca -5 (α (5) β(1))的亲和力增加，88%的VCAM-1粘附依赖于vca -4 (α (4) β(1))的亲和力增加。虽然从可溶性配体的结合判断，趋化素不能诱导整合素亲和力的增加，但共聚焦显微镜实验显示，整合素聚集导致的价增加是趋化素刺激巨噬细胞粘附的机制。PI3K， Akt和p38被认为是chemerin刺激粘附的关键信号介质。趋化素可以快速刺激巨噬细胞对细胞外基质蛋白和粘附分子的粘附，再加上其促进趋化的能力，这一发现表明，趋化素在炎症部位的巨噬细胞募集和保留中发挥了新的作用。中华免疫学杂志，2010,18(5):728- 739。
Chemerin is a potent macrophage chemoattractant protein. We used murine peritoneal exudate cells (PECs) in adhesion, flow cytometry, and confocal microscopy assays to test the hypothesis that chemerin can also contribute to inflammation by promoting macrophage adhesion. Chemerin stimulated the adhesion of PECs to the extracellular matrix protein fibronectin and to the adhesion molecule VCAM-1 within a minute, with an EC50 of 322 and 196 pM, respectively. Experiments using pertussis toxin and PECs from ChemR23(-/-) mice demonstrated that chemerin stimulated the adhesion of macrophages via the Gi protein-coupled receptor ChemR23. Blocking Abs against integrin subunits revealed that 89% of chemerin-stimulated adhesion to fibronectin was dependent on increased avidity of the integrin VLA-5 (alpha(5)beta(1)) and that 88% of adhesion to VCAM-1 was dependent on increased avidity of VLA-4 (alpha(4)beta(1)). Although chemerin was unable to induce an increase in integrin affinity as judged by the binding of soluble ligand, experiments using confocal microscopy revealed an increase in valency resulting from integrin clustering as the mechanism responsible for chemerin-stimulated macrophage adhesion. PI3K, Akt, and p38 were identified as key signaling mediators in chemerin-stimulated adhesion. The finding that chemerin can rapidly stimulate macrophage adhesion to extracellular matrix proteins and adhesion molecules, taken together with its ability to promote chemotaxis, suggests a novel role for chemerin in the recruitment and retention of macrophages at sites of inflammation. The Journal of Immunology, 2010, 185: 3728-3739.