Truncation of CXCL12 by CD26 reduces its CXC chemokine receptor 4-and atypical chemokine receptor 3-dependent activity on endothelial cells and lymphocytes
Truncation of CXCL12 by CD26 reduces its CXC chemokine receptor 4-and atypical chemokine receptor 3-dependent activity on endothelial cells and lymphocytes
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DOI：
10.1016/j.bcp.2017.03.009
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发表时间：
2017-05-15
影响因子：
5.8
通讯作者：
Proost, Paul
中科院分区：
文献类型：
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作者：
Janssens, Rik;Mortier, Anneleen;Proost, Paul
趋化因子CXCL 12或基质细胞衍生因子1/SDF-1通过G蛋白偶联的CXC趋化因子受体4（CXCR 4）吸引造血祖细胞和成熟白细胞。此外，它与非典型趋化因子受体3（ACKR 3或CXCR 7）和糖胺聚糖相互作用。CXCL12活性通过CD26/二肽基肽酶4的翻译后切割来调节，该酶去除两个NH2末端氨基酸。CD26截短的CXCL12不诱导单核细胞的钙信号传导或趋化性。重新化学合成CXCL12（3 - 68）用于详细的生物学表征。与未修饰的CXCL1/2相比，CXCL1/2（3 - 68）不再能够通过CXCR4经由肌醇三磷酸（IP3）、Akt或细胞外信号调节激酶1和2（ERK 1/2）来传递信号。有趣的是，CXCL12（3 - 68）通过CXCR4将β-抑制蛋白2募集到细胞膜被消除，而通过ACKR 3保持减弱但显著的β-抑制蛋白募集。CXCL12诱导的内皮细胞迁移和信号转导被CD26完全废除。在小鼠关节内注射后，完整的CXCL12几乎不诱导淋巴细胞迁移。相反，用CD26抑制剂西格列汀口服治疗小鼠降低了血浆中的CD26活性和CXCL12裂解。在西格列汀处理的小鼠中，CXCL 12诱导关节内淋巴细胞浸润的潜力显著增加，并且CXCL 12（3 - 68）在CD26抑制和非抑制条件下均不能诱导迁移。总之，CD26切割使CXCL12通过ACKR3向13-抑制蛋白依赖性募集倾斜，并破坏CXCL12在体内的CXCR4介导的淋巴细胞化学引诱物特性。因此，组织中的药理学CD26阻断可增强CXCL12诱导的炎症。(C)2017爱思唯尔公司All rights reserved.
The chemokine CXCL12 or stromal cell-derived factor 1/SDF-1 attracts hematopoietic progenitor cells and mature leukocytes through the G protein-coupled CXC chemokine receptor 4 (CXCR4). In addition, it interacts with atypical chemokine receptor 3 (ACKR3 or CXCR7) and glycosaminoglycans. CXCL12 activity is regulated through posttranslational cleavage by CD26/dipeptidyl peptidase 4 that removes two NH2-terminal amino acids. CD26-truncated CXCL12 does not induce calcium signaling or chemotaxis of mononuclear cells. CXCL12(3-68) was chemically synthesized de novo for detailed biological characterization. Compared to unmodified CXCL12, CXCL12(3-68) was no longer able to signal through CXCR4 via inositol trisphosphate (IP3), Akt or extracellular signal-regulated kinases 1 and 2 (ERK1/2). Interestingly, the recruitment of beta-arrestin 2 to the cell membrane via CXCR4 by CXCL12(3-68) was abolished, whereas a weakened but significant beta-arrestin recruitment remained via ACKR3. CXCL12-induced endothelial cell migration and signal transduction was completely abrogated by CD26. Intact CXCL12 hardly induced lymphocyte migration upon intra-articular injection in mice. In contrast, oral treatment of mice with the CD26 inhibitor sitagliptin reduced CD26 activity and CXCL12 cleavage in blood plasma. The potential of CXCL12 to induce intra-articular lymphocyte infiltration was significantly increased in sitagliptin-treated mice and CXCL12(3-68) failed to induce migration under both CD26-inhibiting and non-inhibiting conditions. In conclusion, CD26-cleavage skews CXCL12 towards 13-arrestin dependent recruitment through ACKR3 and destroys the CXCR4-mediated lymphocyte chemoattractant properties of CXCL12 in vivo. Hence, pharmacological CD26-blockade in tissues may enhance CXCL12-induced inflammation. (C) 2017 Elsevier Inc. All rights reserved.