Analysis of fractalkine receptor CX3CR1 function by targeted deletion and green fluorescent protein reporter gene insertion
Analysis of fractalkine receptor CX3CR1 function by targeted deletion and green fluorescent protein reporter gene insertion
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DOI：
10.1128/mcb.20.11.4106-4114.2000
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发表时间：
2000-06-01
影响因子：
5.3
通讯作者：
Littman, DR
中科院分区：
文献类型：
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作者：
Jung, S;Aliberti, J;Littman, DR
七跨膜受体CX（3）CR 1是新型CX 3C趋化因子fractalkine（FKN）（neurotactin）的特异性受体。体外数据表明，FKN的膜锚定以及脱落的可溶性FKN同种型的存在允许粘附和化学吸引性质。在活化的内皮细胞和神经元上的表达将FKN定义为用于炎性病症，特别是中枢神经系统疾病的治疗干预的潜在靶标。为了研究CX（3）CR 1-FKN相互作用的生理功能，我们产生了一种小鼠品系，其中CX，CRI基因被绿色荧光蛋白（GFP）报告基因取代。除了创建突变的CX（3）CR 1基因座，这种方法使我们能够将小鼠CX（3）CR 1表达分配给单核细胞、NK细胞和树突状细胞亚群以及脑小胶质细胞。对CX（3）CR 1缺陷小鼠的分析表明，CX（3）CR 1是唯一的鼠FKN受体。然而，与预期的FKN功能相反，CX（3）CR 1的缺失既不干扰腹膜炎模型中单核细胞的外渗，也不干扰DC对微生物抗原或接触致敏剂的迁移和分化。此外，CX（3）CR 1缺陷的小胶质细胞对周围神经损伤的显著反应表明，在CX（3）CR 1缺失的情况下，神经元-胶质细胞串扰未受损。
The seven-transmembrane receptor CX(3)CR1 is a specific receptor for the novel CX3C chemokine fractalkine (FKN) (neurotactin). In vitro data suggest that membrane anchoring of FKN, and the existence of a shed, soluble FKN isoform allow for both adhesive and chemoattractive properties. Expression on activated endothelium and neurons defines FKN as a potential target for therapeutic intervention in inflammatory conditions, particularly central nervous system diseases. To investigate the physiological function of CX(3)CR1-FKN interactions, we generated a mouse strain in which the CX,CRI gene was replaced by a green fluorescent protein (GFP) reporter gene. In addition to the creation of a mutant CX(3)CR1 locus, this approach enabled us to assign murine CX(3)CR1 expression to monocytes, subsets of NK and dendritic cells, and the brain microglia. Analysis of CX(3)CR1-deficient mice indicates that CX(3)CR1 is the only murine FKN receptor. Yet, defying anticipated FKN functions, absence of CX(3)CR1 interferes neither with monocyte extravasation in a peritonitis model nor with DC migration and differentiation in response to microbial antigens or contact sensitizers. Furthermore, a prominent response of CX(3)CR1-deficient microglia to peripheral nerve injury indicates unimpaired neuronal-glial cross talk in the absence of CX(3)CR1.