The atypical chemokine receptor CCX-CKR scavenges homeostatic chemokines in circulation and tissues and suppresses Th17 responses
The atypical chemokine receptor CCX-CKR scavenges homeostatic chemokines in circulation and tissues and suppresses Th17 responses
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DOI：
10.1182/blood-2010-01-264390
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发表时间：
2010-11-18
期刊：
影响因子：
20.3
通讯作者：
McColl, Shaun R.
中科院分区：
文献类型：
--
作者：
Comerford, Iain;Nibbs, Robert J. B.;McColl, Shaun R.
我们之前的体外研究表明，非典型趋化因子受体CCX-CKR是CCR7配体稳态趋化因子的清除剂。在本研究中，我们建立了CCX-CKR-/-小鼠，并在体内证实了这种清道夫功能。与野生型小鼠相比，CCX-CKR-/-小鼠血液中CCL21蛋白水平增加了5倍，周围淋巴结中CCL19和CCL21蛋白水平增加了2~3倍。用完全弗氏佐剂(CFA)乳化的MOG(35-55)多肽免疫小鼠，观察这些蛋白的增加对免疫的影响。随后在CCX-CKR-/-与野生型小鼠相比，随着动力学和严重程度的增强，出现了特征性的瘫痪。尽管有这种影响，CCX-CKR-/-小鼠引流淋巴结中的抗原特异性免疫反应减弱。相反，疾病的较早发作与CCX-CKR-/-脾中T细胞的增强启动以及CD4(+)T细胞反应向Th17而不是Th1倾斜有关。这与免疫后CCX-CKR-/-脾IL-23表达增加和中枢神经系统CCL21水平升高有关。全身注射中和抗CCL21抗体可逆转CCX-CKR-/-小鼠的早期发病。因此，通过调节体内稳态趋化因子的生物利用度，CCX-CKR影响体内适应性免疫反应的定位、动力学和性质。(《血色》2010；116(20)：4130-4140)
Our previous in vitro studies led to proposals that the atypical chemokine receptor CCX-CKR is a scavenger of CCR7 ligand homeostatic chemokines. In the present study, we generated CCX-CKR-/- mice and confirm this scavenger function in vivo. Compared with wild-type mice, CCX-CKR-/- have a 5-fold increase in the level of CCL21 protein in blood, and 2- to 3-fold increases in CCL19 and CCL21 in peripheral lymph nodes. The effect of these protein increases on immunity was investigated after immunization with MOG(35-55) peptide emulsified in complete Freund adjuvant (CFA). The subsequent characteristic paralysis develops with enhanced kinetics and severity in CCX-CKR-/- versus wild-type mice. Despite this effect, antigen-specific immune responses in the draining lymph nodes are diminished in CCX-CKR-/- mice. Instead, the earlier onset of disease is associated with enhanced T-cell priming in the CCX-CKR-/- spleen and a skewing of CD4(+) T-cell responses toward Th17 rather than Th1. This observation correlates with in-creased expression of IL-23 in the CCX-CKR-/- spleen and increased CCL21 levels in the central nervous system postimmunization. The early onset of disease in CCX-CKR-/- mice is reversed by systemic administration of neutralizing anti-CCL21 antibodies. Thus, by regulating homeostatic chemokine bioavailability, CCX-CKR influences the localization, kinetics, and nature of adaptive immune responses in vivo. (Blood.2010;116(20):4130-4140)