CXC chemokine ligand 4 (CXCL4) down-regulates CC chemokine receptor expression on human monocytes
CXC chemokine ligand 4 (CXCL4) down-regulates CC chemokine receptor expression on human monocytes
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DOI：
10.1177/1753425910388833
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发表时间：
2012-02
期刊：
影响因子：
3.2
通讯作者：
Franziska Schwartzkopff;F. Petersen;T. A. Grimm;E. Brandt
中科院分区：
文献类型：
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作者：
Franziska Schwartzkopff;F. Petersen;T. A. Grimm;E. Brandt
在急性炎症期间，单核细胞在消除入侵的微生物和促进伤口愈合方面至关重要。CC趋化因子的募集是将单核细胞靶向炎症组织的重要步骤。然而，相应的趋化因子受体的细胞表面表达受到各种内源性刺激的调节，这些内源性刺激迄今尚未被全面鉴定。我们报告了血小板衍生的CXC趋化因子配体4（CXCL 4），一种已知的人类单核细胞激活剂，诱导CC趋化因子受体（CCR）1，-2和-5的下调，导致单核细胞向这些受体的同源CC趋化因子配体（CCL）的趋化性迁移严重受损。有趣的是，CXCL 4介导的CCR 1、CCR 2和CCR 5的下调强烈依赖于趋化因子刺激TNF-α自分泌/旁分泌释放的能力。反过来，TNF-α诱导CCL 3和CCL 4的分泌，这两种趋化因子对CCR 1和CCR 5具有选择性，而CCR 2配体CCL 2的分泌是TNF-α非依赖性的。CXCL 4刺激的单核细胞的培养上清液及其趋化因子富集的制剂再现CXCL 4诱导的CCR下调。总之，CXCL 4可能通过刺激自分泌、受体脱敏趋化因子配体的释放，作为单核细胞迁移的选择性调节因子。我们的研究结果强调了CXCL 4在早期炎症过程中血小板和单核细胞之间的相互作用中的协调作用。
During acute inflammation, monocytes are essential in abolishing invading micro-organisms and encouraging wound healing. Recruitment by CC chemokines is an important step in targeting monocytes to the inflamed tissue. However, cell surface expression of the corresponding chemokine receptors is subject to regulation by various endogenous stimuli which so far have not been comprehensively identified. We report that the platelet-derived CXC chemokine ligand 4 (CXCL4), a known activator of human monocytes, induces down-regulation of CC chemokine receptors (CCR) 1, −2, and −5, resulting in drastic impairment of monocyte chemotactic migration towards cognate CC chemokine ligands (CCL) for these receptors. Interestingly, CXCL4-mediated down-regulation of CCR1, CCR2 and CCR5 was strongly dependent on the chemokine’s ability to stimulate autocrine/paracrine release of TNF-α. In turn, TNF-α induced the secretion CCL3 and CCL4, two chemokines selective for CCR1 and CCR5, while the secretion of CCR2-ligand CCL2 was TNF-α-independent. Culture supernatants of CXCL4-stimulated monocytes as well as chemokine-enriched preparations thereof reproduced CXCL4-induced CCR down-regulation. In conclusion, CXCL4 may act as a selective regulator of monocyte migration by stimulating the release of autocrine, receptor-desensitizing chemokine ligands. Our results stress a co-ordinating role for CXCL4 in the cross-talk between platelets and monocytes during early inflammation.