Chemokine interactome mapping enables tailored intervention in acute and chronic inflammation
Chemokine interactome mapping enables tailored intervention in acute and chronic inflammation
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DOI：
10.1126/scitranslmed.aah6650
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发表时间：
2017-04-05
影响因子：
17.1
通讯作者：
Weber, Christian
中科院分区：
文献类型：
--
作者：
von Hundelshausen, Philipp;Agten, Stijn M.;Weber, Christian
趋化因子协调白细胞运输并在健康和疾病中发挥作用。趋化因子在特定微环境中的异嗜性相互作用可以放大、抑制或调节其活性;然而，尚未对趋化因子相互作用组进行系统评价。我们使用免疫配体印迹和表面等离子体共振，以获得一个全面的地图趋化因子-趋化因子的相互作用，并确认其特异性。结构-功能分析表明，趋化因子的活性可以增强CC型异源二聚体，但抑制CXC型异源二聚体。通过CCL 5-CCL 17诱导的受体异聚化或通过CCL 5-CXCL 4的辅助蛋白聚糖结合在细胞表面的受体保留实现功能协同作用。相反，抑制活性依赖于构象变化（在CXCL 12中），影响受体信号传导。专性CC型异二聚体显示出高功效和效力，并驱动急性肺损伤和动脉粥样硬化，这些过程被特异性CCL 5衍生肽抑制剂或相互作用缺陷型CXCL 4变体的敲入所废除。CCL 17缺陷的动脉粥样硬化保护作用通过CCL 5衍生肽破坏CCL 5-CCL 17异二聚体进行表型模拟，而CCL 5 α-螺旋肽模拟对CXCL 12驱动的血小板聚集的抑制作用。因此，特异性趋化因子异源二聚体的形成差异性地决定了功能活性，并且可以用于治疗靶向。
Chemokines orchestrate leukocyte trafficking and function in health and disease. Heterophilic interactions between chemokines in a given microenvironment may amplify, inhibit, or modulate their activity; however, a systematic evaluation of the chemokine interactome has not been performed. We used immunoligand blotting and surface plasmon resonance to obtain a comprehensive map of chemokine-chemokine interactions and to confirm their specificity. Structure-function analyses revealed that chemokine activity can be enhanced by CC-type heterodimers but inhibited by CXC-type heterodimers. Functional synergism was achieved through receptor heteromerization induced by CCL5-CCL17 or receptor retention at the cell surface via auxiliary proteoglycan binding of CCL5-CXCL4. In contrast, inhibitory activity relied on conformational changes (in CXCL12), affecting receptor signaling. Obligate CC-type heterodimers showed high efficacy and potency and drove acute lung injury and atherosclerosis, processes abrogated by specific CCL5-derived peptide inhibitors or knock-in of an interaction-deficient CXCL4 variant. Atheroprotective effects of CCL17 deficiency were phenocopied by a CCL5-derived peptide disrupting CCL5-CCL17 heterodimers, whereas a CCL5 alpha-helix peptide mimicked inhibitory effects on CXCL12-driven platelet aggregation. Thus, formation of specific chemokine heterodimers differentially dictates functional activity and can be exploited for therapeutic targeting.